Heterobiaryl derivatives

ABSTRACT

Heterobiaryl derivatives of the formula 
     
         R.sub.1 NH--X.sub.1 --X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 
    
      --Y 4  --E                                             (I) 
     wherein 
     R 1 , X 1  to X 3  and Y 1  to Y 4  are as defined herein, the tautomers, stereoisomers and mixtures thereof, and the salts, particularly the physiologically acceptable salts, thereof with organic or inorganic acids or bases. The derivatives have valuable pharmacological properties, such as inhibiting cell-cell aggregation and cell-matrix interactions.

This is a division of application Ser. No. 07/961,135, filed Oct. 14,1992, now U.S. Pat. No. 5,418,233.

The invention relates to heterobiaryl derivatives of general formula

    R.sub.1 NH--X.sub.1 --X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 --Y.sub.4 --E                                             (I)

with the exception of2-guanidino-4-[3-[3-(methoxycarbonyl)propyl]-phenyl]-1,3-thiazole (seeC.A. 103, 71307m (1985)) and2-guanidino-4-[6-[(methoxycarbonyl)-methyl]-pyrid-2-yl]-1,3-thiazole(see EP-A-417751), which are histamine receptor antagonists,

the tautomers, stereoisomers, including mixtures thereof, and the saltsthereof, more particularly the physiologically acceptable salts thereofwith inorganic or organic acids or bases which have, inter alia,valuable pharmacological properties, preferably aggregation-inhibitingeffects, pharmaceutical compositions containing these compounds andprocesses for preparing them.

In the above general formula I

R₁ denotes a hydrogen atom, an alkyl, hydroxy, amino, alkoxycarbonyl,aralkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl or arylcarbonyl groupin which the alkyl and alkoxy moieties may each contain 1 to 4 carbonatoms, an alkenyloxycarbonyl group having a total of 4 to 6 carbonatoms, a phosphono, O-alkylphosphono, dialkylphosphoryl orR'--CO--O--(R"CH)--O--CO-- group, wherein

R' represents a C₁₋₅ -alkyl group, a cycloalkyl, cycloalkylalkyl, arylor aralkyl group and

R" denotes a hydrogen atom, a C₁₋₅ -alkyl group, a cycloalkyl orarylalkyl group,

X₁ denotes a C₁₋₃ -alkylene group, a --C(═NH)--, --C(═NH)--NH-- or--C(═NH)--NH--CO-- group, whilst the carbon atom of the --C(═NH)-- groupin the above-mentioned groups is linked to the nitrogen atom of the R₁NH-- group,

X₂ denotes a phenylene, pyridinylene, pyrazinylene, pyrimidinylene orpyridazinylene group, each of which may be mono- or disubstituted in thecarbon skeleton by fluorine, chlorine, bromine or iodine atoms, byalkyl, aralkyl, aryl, pyridylalkyl, hydroxy, alkoxy, aralkoxy,pyridylalkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, amino,alkylamino, dialkylamino, alkylcarbonylamino, arylcarbonylamino,alkylsulphonylamino, arylsulphonylamino, aralkylamino,aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,R₂ -, R₂ CO-alkyl or R₃ CO--CHR₄ --(CH₂)₁ --NHCO-alkyl groups, whereinthe substituents may be identical or different and additionally in oneof the above-mentioned 6-membered heteroaromatic groups containing oneor two nitrogen atoms, one or two --N═CH-- groups may be replaced by oneor two --NR₅ --CO-- groups, wherein

1 represents the number 0 or 1,

R₂ represents an azetidino, pyrrolidino, piperidino orhexamethyleneimino group, whilst the methylene group in the 4-positionof a piperidino group may additionally be replaced by an --O--, --S--,--SO--, --SO₂ --, --NH--, --N(alkyl)--, --N(CHO)--, --N(COalkyl)-- or--N(COaryl)-- group,

R₃ denotes a hydroxy group or a C₁₋₅ -alkoxy group wherein the alkoxymoiety in the 1-, 2- or 3-position may be substituted by an aryl orpyridyl group or in the 2- or 3-position by a pyrrolidino, piperidino,hexamethyleneimino, 2-oxo-1-pyrrolidinyl, morpholino or thiomorpholinogroup,

R₄ denotes a hydrogen atom, a straight-chained or branched C₁₋₆ -alkylgroup which may be substituted by a hydroxy, mercapto, alkylmercapto,amino, R₃ CO--, aminocarbonyl, phenyl, indolyl or imidazolyl group,whilst R₃ is as hereinbefore defined and the phenyl group may besubstituted by a fluorine, chlorine or bromine atom or by a hydroxy oramino group, and

R₅ denotes a hydrogen atom, an alkyl, aralkyl, aryl, pyridylalkyl,aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,R₂ CO-alkyl or R₃ CO--CHR₄ --(CH₂)₁ --NHCO-alkyl group, wherein 1, R₂,R₃ and R₄ are as hereinbefore defined,

a thiophenylene, thiazolylene or thiadiazolylene group,

X₃ has the meanings given for X₂ hereinbefore, with the proviso that X₃does not represent a thiophenylene, thiazolylene or thiadiazolylenegroup and at least one of the groups X₂ or X₃ denotes one of theabove-mentioned heteroaromatic groups, and X₃ denotes a1,2,4-triazinylene group which may be substituted in the carbon skeletonby a fluorine, chlorine, bromine or iodine atom or by an alkyl, aralkyl,aryl, pyridylalkyl, hydroxy, alkoxy, aralkoxy, pyridylalkoxy,alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, amino, alkylamino,dialkylamino, alkylcarbonylamino, arylcarbonylamino,alkylsulphonylamino, arylsulphonylamino, aralkylamino,aminocarbonylalkyl, alkylaminocarbonylalkyl, dialkylaminocarbonylalkyl,R₂ -, R₂ CO-alkyl or R₃ CO--CHR₄ --(CH₂)₁ --NHCO-alkyl group, wherein 1,R₂, R₃ and R₄ are as hereinbefore defined and at the same time in a1,2,4-triazinylene group mentioned above one or two --N═CH-- groups maybe replaced by one or two --NR₅ --CO-- groups, wherein R₅ is defined ashereinbefore and additionally in one of the rings containing an --NR₅--CO-- group mentioned above in the definition of group X₃, R₅ maydenote a bond to the group X₂ or, if Y₁ denotes a bond, R₅ may denote abond to the group Y₂,

Y₁ denotes a bond, an --O--, --S--, --SO--, --SO₂ --, --CO--, --NR₆ --,--NR₆ CO--, --CONR₆ --, --SO₂ NR₆ -- or --NR₆ SO₂ -- group, whilst

R₆ denotes a hydrogen atom, a C₁₋₃ -alkyl group or an aralkyl group,

or an --OCH₂ CO-- group, if Y₂ denotes a bond and Y₃ is a piperidinylenegroup,

Y₂ denotes a bond, a straight-chained or branched C₁₋₆ -alkylene group,a straight-chained or branched alkenylene or alkynylene group eachhaving 2 to 6 carbon atoms, whilst the double bond may not be linkeddirectly to an oxygen, sulphur or phosphorus atom of the groups Y₁, Y₃or E and the triple bond may not be directly linked to a heteroatom ofthe groups Y₁, Y₃ or E, or Y₂ may denote a C₃₋₇ -cycloalkylene group oran arylene group optionally mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms or by alkyl, hydroxy, alkoxy,alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, amino,alkylcarbonylamino or alkylsulphonylamino groups, wherein thesubstituents may be identical or different,

Y₃ denotes a bond, a --CO-- or --CONR₆ -- group or, if a heteroatom ofgroup Y₁ is not bound to the same carbon atom of group Y₂ as the groupY₃, Y₃ may denote an --O--, --S--, --SO--, --SO₂ --, --NR₆ CO-- or --NR₇-- group, whilst

R₇ denotes a hydrogen atom, an alkyl, aralkyl, formyl, alkylcarbonyl,arylcarbonyl, aralkylcarbonyl, alkylsulphonyl, arylsulphonyl oraralkylsulphonyl group,

a group of the formula ##STR1## wherein W denotesa >CH--, >C(OH)--, >CH--O--, >C═CH-- or >C(CH₂ COR₃)-- group wherein R₃is as hereinbefore defined, m and n in each case represent the numbers1, 2 or 3 but m+n must represent the number 2, 3, 4, 5 or 6, and odenotes the number 2 or 3, whilst in the above-mentioned rings amethylene group may additionally be replaced by a carbonyl group or, ifthe methylene group is not adjacent to a nitrogen atom, it may besubstituted by a hydroxy group, and generally an oxygen or sulphur atomof the group Y₃ may not directly follow an oxygen or sulphur atom or aCO-- group of the group Y₁ and an oxygen atom or a sulphenyl orsulphinyl group of the group Y₃ may not directly follow a nitrogen atomof the group Y₁ and a CO-- group of the group Y₃ may not directly followan --O--, --S--, --SO-- or --SO₂ -- group of the group Y₁,

Y₄ denotes a bond, a straight-chained or branched C₁₋₄ -alkylene groupor an arylene group optionally mono- or disubstituted by fluorine,chlorine, bromine or iodine atoms or by alkyl, hydroxy, alkoxy,alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, amino,alkylcarbonylamino or alkylsulphonylamino groups, whilst thesubstituents may be identical or different, and E denotes a sulpho,5-tetrazolyl, phosphono, O-alkyl-phosphono, dialkylphosphoryl,R'--CO--O--(R"CH)--O--CO--, R"'CO-- or R'O--CO--O--(R"CH)--O--CO--group, wherein

R' and R" are as hereinbefore defined and

R"' denotes a hydroxy group, a C₁₋₅ -alkoxy group in which the alkoxymoiety may be substituted in the 1-, 2- or 3-position by an aryl orpyridyl group or in the 2- or 3-position by a pyrrolidino, piperidino,hexamethyleneimino, 2-oxo-1-pyrrolidinyl, morpholino or thiomorpholinogroup, an arylalkenyloxy group having 3 or 4 carbon atoms in the alkenylmoiety, a cycloalkoxy or cycloalkylalkoxy group,

and at least one of the groups Y₁, Y₂, Y₃ or Y₄ does not represent abond and the group E may not directly follow a heteroatom of groups Y₁or Y₃,

whilst unless otherwise stated,

the term "an aryl or arylene group" denotes a phenyl or phenylene groupoptionally mono-, di- or trisubstituted by fluorine, chlorine, bromineor iodine atoms or by alkyl, trifluoromethyl, nitro, amino, alkylamino,dialkylamino, alkanoylamino, alkylsulphonylamino, aminosulphonyl,alkylaminosulphonyl, dialkylaminosulphonyl, hydroxy, alkoxy, carboxy,alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylsulphenyl, alkylsulphinyl or alkylsulphonyl groups, wherein thesubstituents may be identical or different, and

the above-mentioned alkyl, alkylene or alkoxy moieties may each contain1 to 3 carbon atoms, the cycloalkyl and cycloalkoxy moieties may eachcontain 3 to 7 carbon atoms and the alkanoyl moieties may contain 1 to 4carbon atoms.

However, preferred compounds of general formula I above are thosewherein

R₁ denotes a hydrogen atom, a C₁₋₄ -alkyl group or an alkoxycarbonylgroup having a total of 2 to 5 carbon atoms optionallyphenyl-substituted in the alkoxy moiety, a phosphono group, anO-alkyl-phosphono or dialkylphosphoryl group wherein each alkyl moietymay contain 1 or 2 carbon atoms, or an R'--CO--O--(R"CH)--O--CO-- group,wherein

R' denotes a C₁₋₄ -alkyl group or a C₅₋₆ -cycloalkyl group and

R" denotes a hydrogen atom or a methyl group,

X₁ denotes a C₁₋₂ -alkylene group or a --C(═NH)-- group,

X₂ denotes a phenylene, pyridinylene, pyrazinylene, pyrimidinylene orpyridazinylene group each of which may be substituted in the carbonskeleton by a fluorine, chlorine, bromine or iodine atom or by an alkyl,amino, hydroxy, alkoxy, pyrrolidino, piperidino, morpholino,thiomorpholino or N-acetylpiperazino group and wherein the alkyl oralkoxy moiety may contain 1 or 2 carbon atoms, or a thiazolylene group,

X₃ has the meanings given for X₂ hereinbefore with the proviso that X₃does not represent a thiazolylene group and at least one of the groupsX₂ or X₃ denotes one of the above-mentioned heteroaromatic groups, andX₃ denotes a 1,2,4-triazinylene group, whilst in the heteroaromaticrings mentioned in the definition of the group X₃ hereinbefore, one ortwo --N═CH-- groups may simultaneously be replaced by one or two --NR₅--CO-- groups, wherein

R₅ denotes a hydrogen atom, an alkyl, phenyl, benzyl,aminocarbonylalkyl, alkylaminocarbonyl-alkyl, dialkylaminocarbonylalkyl,R₂ CO-alkyl or R₃ CO--CHR₄ --NHCO-alkyl group wherein the alkyl moietymay contain 1 to 3 carbon atoms, R₂ denotes a pyrrolidino, piperidino orhexamethyleneimino group wherein the methylene group in the 4-positionof a piperidino group may additionally be replaced by an --O--, --S--,--NH--, --N(methyl)--, --NHCO-- or --N(COCH₃)-- group, and R₅additionally, in one of the rings containing an --NR₅ CO-- groupmentioned in the definition of the group X₃, denotes a bond to the groupX₂ or, if Y₁ is a bond, to the group Y₂,

R₃ denotes a hydroxy group or a C₁₋₅ -alkoxy group wherein the alkoxymoiety may be substituted in the 1- or 2-position by an aryl or pyridylgroup or in the 2-position by a morpholino or thiomorpholino group, and

R₄ denotes a C₁₋₄ -alkyl group which may be substituted in the 1- or2-position by a phenyl or R₃ CO-- group, wherein R₃ is as hereinbeforedefined and the phenyl group may be substituted by a chlorine or bromineatom or by a hydroxy or amino group,

Y₁ denotes a bond, an --O--, --CO--, --NH--, --NCH₃ --, --CONH--,--CONCH₃ -- or --SO₂ NH-- group or an --OCH₂ CO-- group if Y₂ denotes abond and Y₃ denotes a piperidinylene group,

Y₂ denotes a bond, a straight-chained or branched C₁₋₆ -alkylene group,a straight-chained or branched C₂₋₆ -alkenylene group, in which thedouble bond may not be directly connected to an oxygen, sulphur orphosphorus atom of the groups Y₁, Y₃ or E, a cyclohexylene group or aphenylene group optionally substituted by a fluorine, chlorine orbromine atom or by a methyl group,

Y₃ denotes a bond, a --CO--, --CONH-- or --CONCH₃ -- group or, if aheteroatom of the group Y₁ is not bound to the same carbon atom of thegroup Y₂ as the group Y₃, Y₃ may also denote an --O--, --NH--,--N(COCH₃)--, --N(benzoyl)-- or --N(SO₂ CH₃)-- group,

a group of the formula ##STR2## wherein W denotesa >CH--, >C(OH)--, >CH--O--, >C═CH-- or >C(CH₂ COR₃)-- group, wherein R₃is defined as hereinbefore, m and n each represent the numbers 1, 2 or3, but m+n must represent the number 3 or 4, and

o denotes the number 2, whilst in the above-mentioned rings a methylenegroup may additionally be replaced by a carbonyl group or, if themethylene group is not adjacent to a nitrogen atom, it may besubstituted by a hydroxy group, and generally an oxygen atom of thegroup Y₃ may not directly follow an oxygen atom or a CO group of thegroup Y₁ and an oxygen atom of the group Y₃ may not directly follow anitrogen atom of the group Y₁ and a CO group of the group Y₃ may notdirectly follow an --O-- group of the group Y₁,

Y₄ denotes a bond, a straight-chained or branched C₁₋₄ -alkylene groupor a phenylene group optionally substituted by a fluorine, chlorine orbromine atom or by a methyl group and

E denotes a sulpho, 5-tetrazolyl, phosphono, O-methyl-phosphono,R'--CO--O--(R"CH)--O--CO--, --R"'CO-- or R'O--CO--O--(R"CH)--O--CO--group, wherein

R' and R" are as hereinbefore defined and

R"' denotes a hydroxy group, a C₁₋₅ -alkoxy group in which the alkoxymoiety may be substituted in the 1- or 2-position by a phenyl or pyridylgroup or in the 2- or 3-position by a pyrrolidino, piperidino,hexamethyleneimino, morpholino or thiomorpholino group, a C₄₋₇-cycloalkoxy group, a cycloalkylalkoxy group having 4 to 7 carbon atomsin the cycloalkyl moiety and 1 to 3 carbon atoms in the alkoxy moiety,or a phenylallyloxy group,

and at least one of the groups Y₁, Y₂, Y₃ or Y₄ does not represent abond and the group E may not directly follow a heteroatom of groups Y₁or Y₃,

the tautomers, stereoisomers, mixtures and salts thereof.

However, particularly preferred compounds of the above general formulaare those wherein

R₁ denotes a hydrogen atom, a C₁₋₄ -alkyl group, an alkoxycarbonyl grouphaving a total of 2 to 5 carbon atoms, a benzyloxycarbonyl,dimethylphosphoryl, diethylphosphoryl or R'--CO--O--(R"CH)--O--CO--group, wherein

R' denotes a methyl or ethyl group and

R" denotes a hydrogen atom or a methyl group,

X₁ denotes a methylene group or a --C(═NH)-- group,

X₂ denotes a phenylene, pyridinylene, pyrazinylene, pyrimidinylene orpyridazinylene group each of which may be substituted in the carbonskeleton by a fluorine, chlorine or bromine atom or by a methyl,hydroxy, methoxy, ethoxy, amino, dimethylamino, pyrrolidino, piperidino,morpholino, thiomorpholino or N-acetylpiperazino group, or athiazolylene group,

X₃ has the meanings given for X₂ hereinbefore with the proviso that X₃does not represent a thiazolylene group and at least one of the groupsX₂ or X₃ denotes one of the above-mentioned heteroaromatic groups, andX₃ denotes a 1,2,4-triazinylene group, whilst in the heteroaromaticrings mentioned hereinbefore in the definition of the group X₃, an--N═CH-- group may simultaneously be replaced by an --NR₅ --CO-- group,wherein

R₅ denotes a hydrogen atom, a methyl, ethyl, phenyl, benzyl,aminocarbonylmethyl, dimethylaminocarbonyl-methyl, R₂ CO-methyl or R₃CO--CHR₄ --NHCO-methyl group, wherein R₂ is a morpholino group,

R₃ is a hydroxy group or a C₁₋₃ -alkoxy group and

R₄ denotes a methyl or benzyl group and R₅ may additionally represent,in a ring containing an --NR₅ --CO-- group mentioned hereinbefore in thedefinition of the group X₃, a bond to the group X₂ or, if Y₁ denotes abond, to the group Y₂,

Y₁ denotes a bond, an --O--, --CO--, --NH--, --NCH₃ --, --CONH--,--CONCH₃ -- or --SO₂ NH-- group or an --OCH₂ CO-- group if Y₂ denotes abond and Y₃ is a piperidinylene group,

Y₂ denotes a bond, a straight-chained or branched C₁₋₆ -alkylene group,a straight-chained or branched C₂₋₆ -alkenylene group, wherein thedouble bond may not be directly linked to an oxygen, sulphur orphosphorus atom of the groups Y₁, Y₃ or E, or Y₂ represents acyclohexylene or phenylene group,

Y₃ denotes a bond, a --CO--, --CONH-- or --CONCH₃ -- group or, if aheteroatom of group Y₁ is not bound to the same carbon atom of the groupY₂ as the group Y₃, Y₃ may also denote an --O--, --NH--, --N(COCH₃)--,--N(benzoyl)-- or --N(SO₂ CH₃)-- group,

a group of the formula ##STR3## wherein W representsa >CH--, >C(OH)--, >CH--O--, >C=CH-- or >C(CH₂ COR₃)-- group, wherein R₃is as hereinbefore defined,

m and n each denote the numbers 1, 2 or 3, but m+n must represent thenumber 3 or 4, and

o denotes the number 2, whilst in the above-mentioned rings a methylenegroup may additionally be replaced by a carbonyl group, and generally anoxygen atom of the group Y₃ may not directly follow an oxygen atom or aCO-- group of the group Y₁ and an oxygen atom of the group Y₃ may notdirectly follow a nitrogen atom of the group Y₁ and a CO group of thegroup Y₃ may not directly follow an --O-- group of the group Y₁,

Y₄ denotes a bond, a straight-chained or branched C₁₋₄ -alkylene groupor a phenylene group and

E denotes a sulpho, 5-tetrazolyl, phosphono, O-methyl-phosphono orR"'CO-- group, wherein

R" denotes a hydroxy group, a C₁₋₄ -alkoxy group, a cycloalkoxy orcycloalkoxymethoxy group each having 5 or 6 carbon atoms in thecycloalkoxy moiety, or a benzyloxy or pyridylmethoxy group,

at least one of the groups Y₁, Y₂, Y₃ or Y₄ does not represent a bondand the group E may not directly follow a heteroatom of groups Y₁ or Y₃,

the tautomers, stereoisomers and mixtures thereof and the salts thereof.

Particularly preferred compounds of general formula I above, however,are those wherein

R₁ denotes a hydrogen atom or an alkoxycarbonyl group with a total of 2or 3 carbon atoms,

X₁ denotes a methylene group or a --C(═NH)-- group,

X₂ denotes a phenylene group,

X₃ denotes a pyrimidinylene or pyridazinylene group, each of which maybe substituted in the carbon skeleton by a methoxy or morpholino group,whilst in the above-mentioned heteroaromatic rings an --N═CH-- group maysimultaneously be replaced by an --NR₅ --CO-- group, whilst

R₅ denotes a hydrogen atom or a methyl, benzyl ormorpholinocarbonylmethyl group,

Y₁ denotes a bond, an --O--, --CO--, --NH--, --NCH₃ --, --CONH-- or--CONCH₃ -- group,

Y₂ denotes a bond, a straight-chained or branched C₁₋₄ -alkylene groupor a cyclohexylene or phenylene group,

Y₃ denotes a bond, an --O-- group or a group of the formula ##STR4##wherein W denotes a >CH-- or >CH--O-- group,

m and n each denote the numbers 1, 2 or 3, but m+n must represent thenumber 4, and generally an oxygen atom of the group Y₃ may not directlyfollow an oxygen atom or a CO group of the group Y₁ and an oxygen atomof the group Y₃ may not directly follow a nitrogen atom of the group Y₁and a CO group of the group Y₃ may not directly follow an --O-- group ofthe group Y₁,

Y₄ denotes a bond, an alkylene group having 1 or 2 carbon atoms or aphenylene group and

E denotes a carboxy group or an alkoxycarbonyl group having a total of 2to 4 carbon atoms, wherein at least one of the groups Y₁, Y₂, Y₃ or Y₄does not represent a bond and the group E may not directly follow aheteroatom of groups Y₁ or Y₃,

but particularly those compounds of general formula I wherein

R₁ denotes a hydrogen atom or an alkoxycarbonyl group having a total of2 or 3 carbon atoms,

X₁ is a methylene group or a --C(═NH)-- group,

X₂ is a phenylene group,

X₃ is a pyrimidinylene group optionally substituted by a methoxy group,a pyridazinylene group optionally substituted by a methoxy or morpholinogroup, a pyrimidinylene or pyridazinylene group in which an --N═CH--group is replaced by an --NR₅ --CO-- group, wherein

R₅ is a hydrogen atom or a methyl, benzyl or morpholinocarbonylmethylgroup,

Y₁ is a bond or a --CO--, --CONH-- or --CONCH₃ group,

Y₂ is a bond, a straight-chained C₃₋₄ -alkylene group or a cyclohexylenegroup,

Y₃ is a bond or a group of the formula ##STR5## wherein W is a >CH--group,

m and n each denote the numbers 1, 2 or 3, but m+n must represent thenumber 4,

Y₄ denotes a bond or a methylene group and

E is a carboxy group or an alkoxycarbonyl group with a total of 2 or 3carbon atoms, whilst at least one of the groups Y₁, Y₂, Y₃ or Y₄ doesnot denote a bond and the group E may not directly follow a heteroatomof the groups Y₁ or Y₃.

The following compounds are particularly preferred:

6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one,

6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one,

6-[4-[N-(methoxycarbonyl)-amidino]-phenyl]-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one,

6-[4-[N-(ethoxycarbonyl)-amidino]-phenyl]-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one,

2-(4-amidinophenyl)-5-[4-(carboxymethyl)-piperidinocarbonyl]-4-methoxy-pyrimidine,

2-(4-amidinophenyl)-4-methoxy-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine,

4-methoxy-2-[4-[N-(methoxycarbonyl)-amidino]-phenyl]-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine,

6-(4-amidinophenyl)-4-[N-(trans-4-carboxycyclohexyl)-N-methylaminocarbonyl]-2-methyl-(2H)-pyridazin-3-one,

6-(4-amidinophenyl)-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one,

3-(4-amidinophenyl)-5-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-pyridazine,

3-(4-amidinophenyl)-5-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazine,

6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-oneand

6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one,

the tautomers and the salts thereof.

According to the invention the new compounds of general formula I may,for example, be obtained by the following methods known per se:

a) In order to prepare compounds of general formula I wherein E denotesa carboxy group:

Converting a compound of general formula

    R.sub.1 NH--X.sub.1 --X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 --Y.sub.4 --E'                                            (II)

wherein

R₁, X₁ to X₃ and Y₁ to Y₄ are as hereinbefore defined and E', which isbound to a carbon atom, denotes a group which may be converted into acarboxy group by hydrolysis, treatment with acids, thermolysis orhydrogenolysis.

For example, functional derivatives of the carboxyl group such as theunsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters, iminoesters, amidines or anhydrides, or the nitrilegroup may be converted by hydrolysis into a carboxyl group, esters withtertiary alcohols, e.g. the tert.butylester, may be converted by acidtreatment or thermolysis into a carboxyl group and esters witharalkanols, e.g. the benzylester, may be converted by hydrogenolysisinto a carboxyl group, and bis(alkoxycarbonyl)methyl groups may beconverted by hydrolysis or treatment with an acid into abis(hydroxycarbonyl)methyl group which is subsequently decarboxylated.

The hydrolysis is appropriately carried out either in the presence of anacid such as hydrochloric acid, sulphuric acid, phosphoric acid,trichloroacetic acid or trifluoroacetic acid in the presence of a basesuch as lithium hydroxide, sodium hydroxide or potassium hydroxide in asuitable solvent such as water, methanol, water/methanol, ethanol,water/ethanol, water/isopropanol, water/tetrahydrofuran or water/dioxaneat temperatures between -10° C. and 120° C., e.g. at temperaturesbetween ambient temperature and the boiling temperature of the reactionmixture. When hydrolysis is carried out in the presence of an organicacid such as trichloroacetic acid or trifluoroacetic acid, any alcoholichydroxy groups present may simultaneously be converted into acorresponding acyloxy group such as the trifluoroacetoxy group.

If E' in a compound of formula II represents a cyano or aminocarbonylgroup, these groups may also be converted into the carboxyl group with anitrite, e.g. sodium nitrite, in the presence of an acid such assulphuric acid, which may simultaneously also be used as solvent, attemperatures between 0° and 50° C.

If E' in a compound of formula II represents for example thetert.-butyloxycarbonyl group, the tert.-butyl group may also be cleaved,by treatment with an acid such as trifluoroacetic acid, formic acid,p-toluenesulphonic acid, sulphuric acid, phosphoric acid orpolyphosphoric acid, optionally in an inert solvent such as methylenechloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane,preferably at temperatures between -10° C. and 120° C., e.g. attemperatures between 0° and 60° C., or thermally cleaved, optionally inan inert solvent such as methylene chloride, chloroform, benzene,toluene, tetrahydrofuran or dioxane and preferably in the presence of acatalytic amount of an acid such as p-toluenesulphonic acid, sulphuricacid, phosphoric acid or polyphosphoric acid, preferably at the boilingtemperature of the solvent used, e.g. at temperatures between 40° C. and100° C.

If E' in a compound of formula II represents the benzyloxycarbonylgroup, for example, the benzyl group may also be hydrogenolyticallycleaved in the presence of a hydrogenation catalyst such aspalladium/charcoal in a suitable solvent such as methanol, ethanol,ethanol/water, glacial acetic acid, ethyl acetate, dioxane ordimethylformamide, preferably at temperatures between 0° and 50° C.,e.g. at ambient temperature, under a hydrogen pressure of 1 to 10 bar.During hydrogenolysis, other groups may be reduced at the same time,e.g. a nitro group may be reduced to the amino group, a benzyloxy groupto the hydroxy group, or a benzyloxycarbonylamidino group may beconverted into the amidino group.

b) In order to prepare compounds of general formula I wherein the R₁NH--X₁ -- group denotes an amidino group wherein R₁ is a hydrogen atomor a hydroxy, alkyl or amino group:

Reacting a compound of general formula

    Z.sub.1 --C(═NH)--X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 --Y.sub.4 --E                                             (III)

optionally formed in the reaction mixture, wherein

X₂, X₃, Y₁ to Y₄ and E are as hereinbefore defined and Z₁ denotes analkoxy or aralkoxy group such as a methoxy, ethoxy, n-propoxy,isopropoxy or benzyloxy group or an alkylthio or aralkylthio group suchas a methylthio, ethylthio, n-propylthio or benzylthio group or an aminogroup, with an amine of general formula

    R.sub.a --NH.sub.2                                         (IV)

wherein

R_(a) denotes a hydrogen atom or a hydroxy, alkyl or amino group, orwith the acid addition salts thereof.

The reaction is conveniently carried out in a solvent such as methanol,ethanol, n-propanol, water, methanol/water, tetrahydrofuran or dioxaneat temperatures between 0° and 150° C., preferably at temperaturesbetween 20° and 120° C., with a corresponding free amine or with acorresponding acid addition salt such as ammonium carbonate or ammoniumacetate.

A compound of general formula III, for example, is obtained by reactinga corresponding nitrile with a corresponding alcohol such as methanol,ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of anacid such as hydrochloric acid or in the presence of a correspondingalkoxide such as sodium methoxide or sodium ethoxide or by reacting acorresponding amide with a trialkyloxonium salt such astriethyloxonium-tetrafluoroborate in a solvent such as methylenechloride, tetrahydrofuran or dioxane at temperatures between -10° and50° C., but preferably at temperatures between 0° and 20° C., or acorresponding nitrile with hydrogen sulphide, expediently in a solventsuch as pyridine or dimethylformamide and in the presence of a base suchas triethylamine with subsequent alkylation of the thioamide formed witha corresponding alkyl or aralkylhalide.

c) In order to prepare compounds of general formula I wherein the R₁NH--X₁ -- group is an aminoalkyl group:

Reducing a compound of general formula

    NC--X.sub.1' --X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 --Y.sub.4 --E                                                       (V)

wherein

X₂, X₃, Y₁ to Y₄ and E are as hereinbefore defined and X_(1') denotes abond or a C₁₋₂ -alkylene group.

The reduction is preferably carried out in a suitable solvent such asmethanol, methanol/water, methanol/ammonia, methanol/water/ammonia,methanol/hydrochloric acid, ethanol, ether, tetrahydrofuran, dioxane,dimethylformamide or glacial acetic acid in the presence ofcatalytically activated hydrogen, e.g. hydrogen in the presence of Raneynickel, platinum or palladium/charcoal, or in the presence of a metalhydride such as sodium borohydride or lithium borohydride attemperatures between 0° and 100° C., preferably at temperatures between20° and 80° C.

d) In order to prepare compounds of general formula I wherein R₁ denotesan alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl orarylcarbonyl group in which the alkyl and alkoxy moieties may eachcontain 1 to 4 carbon atoms, an alkenyloxycarbonyl group having a totalof 4 to 6 carbon atoms, a phosphono, O-alkyl-phosphono,dialkylphosphoryl or R'--CO--O--(R"CH)--O--CO-- group wherein R' and R"are as hereinbefore defined:

Reacting a compound of general formula

    H.sub.2 N--X.sub.1 --X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 --Y.sub.4 --E                                             (VI)

wherein

X₁ to X₃, Y₁ to Y₄ and E are as hereinbefore defined, with a compound ofgeneral formula

    Z.sub.2 --R.sub.b                                          (VII)

wherein

R_(b) denotes an alkoxycarbonyl, aralkoxycarbonyl, aryloxycarbonyl,alkylcarbonyl or arylcarbonyl group in which the alkyl and alkoxymoieties may each contain 1 to 4 carbon atoms, an alkenyloxycarbonylgroup with a total of 4 to 6 carbon atoms, an R'--CO--O--(R"CH)--O--CO--or dialkylphosphoryl group wherein R' and R" are as hereinbefore definedand,

Z₂ denotes a nucleophilic leaving group such as a halogen atom, e.g. achlorine or bromine atom, or an optionally substituted phenoxy group,e.g. a p-nitrophenoxy group, optionally with subsequent cleaving of oneor two alkyl groups from a dialkylphosphoryl compound thus obtained.

The reaction is expediently carried out in a solvent or mixture ofsolvents such as water, tetrahydrofuran, tetrahydrofuran/water, dioxane,dioxane/water, methylene chloride, chloroform, ethyl acetate ordimethylformamide, appropriately in the presence of a base such assodium carbonate, potassium carbonate or sodium hydroxide solution or inthe presence of a tertiary organic base such as triethylamine,N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine, which maysimultaneously serve as solvent, at temperatures between -30° and 100°C., but preferably at temperatures between -10° and 80° C.

The cleaving of an alkyl group from a dialkylphosphoryl compound thusobtained is carried out, for example, with sodium iodide in a solventsuch as acetone, ethylmethylketone, acetonitrile or dimethylformamide attemperatures between 40° and 150° C., but preferably at temperaturesbetween 60° and 100° C.

The cleaving of both alkyl groups from a dialkylphosphoryl compound thusobtained is carried out, for example, using iodotrimethylsilane,bromotrimethylsilane or chlorotrimethylsilane/sodium iodide in a solventsuch as methylene chloride, chloroform or acetonitrile at temperaturesbetween 0° C. and the boiling temperature of the reaction mixture, butpreferably at temperatures between 20° and 60° C.

e) In order to prepare compounds of general formula I wherein E denotesan R"'CO group where R"' is as hereinbefore defined:

Reacting a compound of general formula

    R.sub.1 NH--X.sub.1 --X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 --Y.sub.4 --E"                                            (VIII)

wherein

R₁, X₁ to X₃ and Y₁ to Y₄ are as hereinbefore defined and E" denotes acarboxy or alkoxycarbonyl group, with an alcohol of general formula

    HO--R"'                                                    (IX)

wherein

R"' is as hereinbefore defined.

The reaction is conveniently carried out in a solvent or mixture ofsolvents such as methylene chloride, dimethylformamide,dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran,benzene/tetrahydrofuran or dioxane, optionally in the presence of anacid such as hydrochloric acid or in the presence of a dehydratingagent, e.g. in the presence of isobutylchloroformate, thionylchloride,trimethylchlorosilane, hydrochloric acid, sulphuric acid,methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride,phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide,dimethylaminopyridine or 1-hydroxybenzotriazole,N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, conveniently at temperaturesbetween 0° and 150° C., preferably at temperatures between 0° and 50° C.

The reaction of a corresponding alkoxy compound of general formula VIIIwith an alcohol of general formula IX is preferably carried out in thealcohol in question as solvent optionally in the presence of anothersolvent such as methylene chloride or ether, preferably in the presenceof an acid such as hydrochloric acid at temperatures between 0° and 100°C., preferably at temperatures between 20° and 80° C.

f) In order to prepare compounds of general formula I wherein Y₁ denotesa --CO-- or --CONR₆ -- group:

Reacting a compound of general formula

    R.sub.1 NH--X.sub.1 --X.sub.2 --X.sub.3 --COOH             (X)

wherein

R₁ and X₁ to X₃ are as hereinbefore defined, with a compound of generalformula

    U--Y.sub.2 --Y.sub.3 --Y.sub.4 --E                         (XI)

wherein

Y₂ to Y₄ and E are as hereinbefore defined and, if Y₂ does not denote abond, U represents an --NR₇ -- group wherein R₇ is as hereinbeforedefined or, if Y₃ denotes one of the cyclic imino groups mentionedhereinbefore and Y₂ denotes a bond, U may also represent a hydrogenatom, or with a reactive derivative thereof.

The reaction is conveniently carried out in a solvent such as methylenechloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran,dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionallyin the presence of an acid activating agent or a dehydrating agent, e.g.in the presence of ethylchloroformate, thionylchloride, phosphorustrichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide,N,N'-dicyclohexyl-carbodiimide/N-hydroxysuccinimide,N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole ortriphenylphosphine/carbon tetrachloride, optionally in the presence ofan inorganic base such as sodium carbonate or a tertiary organic basesuch as triethylamine or pyridine, which may simultaneously serve assolvent, at temperatures between -25° and 150° C., but preferably attemperatures between -10° C. and the boiling temperature of the solventused. The acylation is, however, as described above, preferably carriedout with a corresponding acid halide or acid anhydride, and may also becarried out without a solvent.

g) In order to prepare compounds of general formula I wherein E denotesan R'--CO--O--(R"CH)--O--CO--, R'O--CO--O--(R"CH)--O--CO-- or R"'--CO--group, wherein R' to R"' are as hereinbefore defined:

Reacting a compound of general formula

    R.sub.1 NH--X.sub.1 --X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 --Y.sub.4 --COOH                                          (XII)

wherein

R₁, X₂ to X₃ and Y₁ to Y₄ are as hereinbefore defined, with a compoundof general formula

    Z.sub.3 --R.sub.c                                          (XIII)

wherein

R_(c) denotes an R'--CO--O--(R"CH)--, R'O--CO--O--(R"CH)-- or R"'-group,wherein R' to R"' are as hereinbefore defined, and Z₃ denotes anucleophilic leaving group such as a halogen atom, e.g. a chlorine orbromine atom.

The reaction is conveniently carried out in a solvent such as methylenechloride, tetrahydrofuran, dioxane, dimethylsulphoxide ordimethylformamide, optionally in the presence of a reaction acceleratorsuch as sodium or potassium iodide and preferably in the presence of abase such as sodium carbonate, potassium carbonate or sodium hydroxidesolution or in the presence of a tertiary organic base such asN-ethyl-diisopropylamine or N-methyl-morpholine, which maysimultaneously serve as solvent, or optionally in the presence of silvercarbonate or silver oxide at temperatures between -30° and 100° C., butpreferably at temperatures between -10° and 80° C.

In the reactions described hereinbefore, any reactive groups presentsuch as hydroxy, carboxy, amino, alkylamino or imino groups mayoptionally be protected during the reaction by conventional protectinggroups which are split off again after the reaction.

Examples of protecting groups for a hydroxy group are thetrimethylsilyl, acetyl, benzoyl, tert.-butyl, trityl, benzyl ortetrahydropyranyl group, examples of protecting groups for a carboxylgroup are the trimethylsilyl, methyl, ethyl, tert.butyl, benzyl ortetrahydropyranyl group, and protecting groups for an amino, alkylaminoor imino group include the acetyl, trifluoroacetyl, benzoyl,ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl,methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for theamino group, the phthalyl group.

The optional subsequent cleaving of a protecting group is preferablycarried out by hydrolysis in an aqueous solvent, e.g. in water,isopropanol/water, tetrahydrofuran/water or dioxane/water, in thepresence of an acid such as trifluoroacetic acid, hydrochloric acid orsulphuric acid or in the presence of an alkali metal base such aslithium hydroxide, sodium hydroxide or potassium hydroxide, or by ethersplitting, e.g. in the presence of iodotrimethylsilane, at temperaturesbetween 0° and 100° C., preferably at temperatures between 10° and 50°C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group ispreferably split off by hydrogenolysis, e.g. with hydrogen in thepresence of a catalyst such as palladium/charcoal in a solvent such asmethanol, ethanol, ethyl acetate or glacial acetic acid, optionally withthe addition of an acid such as hydrochloric acid at temperaturesbetween 0° and 50° C., but preferably at ambient temperature, under ahydrogen pressure of 1 to 7 bar, preferably of 3 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of anoxidising agent such as cerium(IV) ammonium nitrate in a solvent such asmethylene chloride, acetonitrile or acetonitrile/water at temperaturesbetween 0° and 50° C., but preferably at ambient temperature.

However, a 2,4-dimethoxybenzyl group is preferably split off intrifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably split off bytreating with an acid such as trifluoroacetic acid or hydrochloric acid,optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl group is preferably split off in the presence of hydrazine ora primary amine such as methylamine, ethylamine or n-butylamine in asolvent such as methanol, ethanol, isopropanol, toluene/water or dioxaneat temperatures between 20° and 50° C.

Moreover, the compounds of general formula I may, as already indicatedhereinbefore, be resolved into the enantiomers and/or diastereomersthereof. Cis/trans mixtures for example may be resolved into the cis-and trans-isomers and chiral compounds may be resolved into theenantiomers.

Thus, for example, the cis/trans mixtures obtained may be separated bychromatography into their cis and trans isomers, the compounds ofgeneral formula I obtained in the form of racemates may be separated byknown methods (see Allinger N. L. and Eliel E. L. in "Topics inStereochemistry", Vol. 6, Wiley Interscience, 1971) into their opticalantipodes and compounds of general formula I having at least 2asymmetric carbon atoms can be separated on the basis of theirphysical-chemical differences into their diastereomers by methods knownper se, e.g. by chromatography and/or fractional crystallisation, and ifthese diastereomers are obtained in racemic form they may subsequentlybe separated into the enantiomers as mentioned above.

Enantiomer separation is preferably achieved by column separation onchiral phases or by recrystallisation from an optically active solventor by reacting with an optically active substance which forms salts orderivatives such as esters or amides with the racemic compound, moreparticularly acids and their activated derivatives or alcohols, andseparating the diastereomeric salt mixture obtained in this way, e.g. onthe basis of different solubilities, whilst the free antipodes may beliberated from the pure diastereomeric salts by the action of suitableagents. Particularly common optically active acids are, for example, theD and L forms of tartaric acid or dibenzoyltartaric acid,di-o-tolyl-tartaric acid, malic acid, mandelic acid camphorsulphonicacid, glutamic acid, aspartic acid or quinic acid. An optically activealcohol might be, for example, (+)- or (-)-menthol and an opticallyactive acyl group in amides might be (+) or (-)-menthyloxycarbonyl.

Moreover, the compounds of formula I obtained may be converted into theacid addition salts thereof, more particularly for pharmaceutical usethe physiologically acceptable salts thereof with inorganic or organicacids. Examples of suitable acids include hydrochloric acid, hydrobromicacid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid,lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the new compounds of formula I thus obtained, should theycontain a carboxyl group, may if desired subsequently be converted intothe addition salts thereof with inorganic or organic bases, moreparticularly for pharmaceutical use into the physiologically acceptableaddition salts thereof. Examples of suitable bases include sodiumhydroxide, potassium hydroxide, ammonia, cyclohexylamine, ethanolamine,diethanolamine and triethanolamine.

The compounds used as starting materials are known from the literaturein some cases or may be obtained by methods known from the literature asdescribed in Examples I to XXIII.

As already mentioned hereinbefore, the new heterobiaryls of generalformula I and the salts thereof, particularly the physiologicallyacceptable addition salts thereof with inorganic or organic acids orbases, have valuable properties. Thus, the compounds of general formulaI wherein R₁ denotes a group which can optionally be cleaved in vivo,e.g. an alkoxycarbonyl group, and E denotes a carboxyl, phosphono,O-alkyl-phosphono or 5-tetrazolyl group or a group which may beconverted in vivo into a carboxyl, sulpho, phosphono, O-alkyl-phosphonoor tetrazolyl group, e.g. an alkoxy-substituted carbonyl group, not onlyhave an antiinflammatory effect which inhibits the breakdown of bone butin particular antithrombotic, antiaggregatory and inhibitory effects ontumours or metastases.

By way of example, the compounds of general formula I were tested fortheir biological effects in the following way:

1. Fibrinogen binding to human thrombocytes

Blood obtained by puncture of an antecubital vein is anticoagulated withtrisodium citrate (final concentration: 13 mM) and centrifuged for 10minutes at 170 *g. The supernatant platelet-rich plasma is placed on aSepharose 2B column (Pharmacia) and eluted with a solution of 90 mMcommon salt, 14 mM trisodium citrate, 5 mM glucose and 50 mMtris(hydroxymethyl)aminomethane, adjusted to pH 7.4. The gel-filteredplatelets (GFP) appearing in front of the plasma proteins are used forthe binding tests.

50 μl of a 60 mM calcium chloride solution, 50 μl of a 0.6 mM adenosinediphosphate solution, 100 μl of substance solution or solvent and 50 μlof fibrinogen solution (containing 3 μg ¹²⁵ I-fibrinogen) are added to750 μl of GFP and incubated for 20 minutes at ambient temperature. Thenon-specific binding is measured in the presence of 3 mg/ml of coldfibrinogen.

900 μl of the incubate are carefully pipetted onto 250 μl of silicon oil(AP 38: AR 20, 1:2 v/v, Wacker Chemie) in Eppendorf vessels andcentrifuged for 2 minutes at 10,000 *g. The aqueous supernatant and someof the oil are removed, the tip of the vessel with the platelet pelletis cut off and the quantity of bound fibrinogen is measured in agamma-counter. The concentration of substance which inhibits fibrinogenbinding by 50% is calculated from a series of concentrations and givenas the IC₅₀.

2. Antithrombotic activity

Method

The thrombocyte aggregation is measured using the Born and Cross method(J. Physiol. 170: 397 (1964)) in platelet-rich plasma taken from healthyvolunteers. To inhibit coagulation the blood is mixed with 3.14% sodiumcitrate in a ratio by volume of 1:10.

Collagen-induced aggregation

The pattern of the decrease in optical density of the plateletsuspension is photometrically measured and recorded after the additionof the aggregation-triggering substance. The rate of aggregation isconcluded from the angle of inclination of the density curve. The pointon the curve where there is maximum light transmittance is used tocalculate the optical density.

The amount of collagen used is as small as possible but sufficient toproduce an irreversible reaction curve. Standard commercial collagenproduced by Hormonchemie of Munich is used. Before the addition of thecollagen the plasma is incubated for 10 minutes with the substance at37° C.

From the measurements obtained an EC₅₀ is determined graphically,indicating a 50% change in the optical density in terms of theinhibition of aggregation.

The Table which follows contains the results found:

    ______________________________________                                                      Fibrinogen                                                                              Inhibition of platelet                                Substance     binding test                                                                            aggregation                                           (Example No.) ID.sub.50 [μM]                                                                       EC.sub.50 [μM]                                     ______________________________________                                        1             0.13      0.42                                                  1(3)          0.20      0.39                                                  1(4)          0.037     0.54                                                  1(7)          4.40      12.00                                                 1(8)          1.70      39.00                                                 1(11)         0.58      1.20                                                  1(14)         0.033     0.10                                                  1(16)         0.055     0.16                                                  1(20)         0.057     0.29                                                  1(18)         0.033*    0.31                                                  1(21)         0.062     0.32                                                  1(30)         0.033*    0.10                                                  2             1.90      0.36                                                  2(1)          3.20      1.90                                                  2(15)         52.00     5.20                                                  2(17)         2.30      1.30                                                  3             2.20      >300.00                                               4             0.37      0.79                                                  5             6.20      3.00                                                  ______________________________________                                         *.sup.125 I fibrinogen was replaced by [.sup.3                                H(3S,5S)-5-[(4amidino-4-biphenylyl)-oxymethyl3-carboxymethyl-2-pyrrolidon

Moreover, when tested on rats, for example, the compound of Example 3showed an antiaggregatory activity two hours after the oraladministration of 10 mg/kg in an ex vivo test carried out with ratplasma in the presence of human thrombocytes.

The new compounds are well tolerated since the intravenousadministration of 30 mg/kg of the compounds of Examples 1, 1(4), 1(16),1(20), 3 and 4 to three mice did not cause any deaths.

In view of their inhibitory effect on cell-cell and cell-matrixinteractions, the new heterobiaryls of general formula I and thephysiologically acceptable addition salts thereof are suitable forcombating or preventing diseases in which smaller or larger clumps ofcells are produced or cell-matrix interactions are involved, e.g. incombating or preventing venous and arterial thrombosis, cerebro-vasculardiseases, pulmonary embolisms, cardiac infarct, arteriosclerosis,osteoporosis and tumour metastasis and for treating genetically causedor acquired disorders of the interaction of cells with one another orwith solid structures. They are also suitable as an accompanying therapyin thrombolysis with fibrinolytics or vascular interventions such astransluminal angioplasty or in the treatment of shock, psoriasis,diabetes and inflammation.

For combating or preventing the above-mentioned diseases, the dose isbetween 0.1 μg and 20 mg/kg of body weight, preferably 1 μg to 10 mg/kgof body weight, in up to 4 doses per day. For this purpose, thecompounds of formula I prepared according to the invention may beformulated, optionally in conjunction with other active substances,together with one or more inert conventional carriers and/or diluents,e.g. with corn starch, lactose, glucose, microcrystalline cellulose,magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid,water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene glycol, stearyl alcohol, carboxymethylcellulose orfatty substances such as hard fat or suitable mixtures thereof, toproduce conventional galenic preparations such as plain or coatedtablets, capsules, powders, suspensions, solutions, sprays orsuppositories.

The Examples which follow are intended to illustrate the invention:

Preparation of the Starting Compounds EXAMPLE I3-(4-Cyanobenzoyl)-2-hydroxy-propionic acid

25 g of 4-cyano-acetophenone and 24 g of glyoxylic acid monohydrate arestirred for 5 hours at 95° C. in a water jet vacuum. A viscous oil isobtained which is dissolved in a mixture of saturated sodium hydrogencarbonate solution and ethyl acetate. The organic phase is separatedoff, the aqueous phase is acidified with 2N hydrochloric acid andextracted several times with ethyl acetate. The combined ethyl acetatephases are washed with water, dried and evaporated down. The residue istriturated with ether, suction filtered and further reacted as a crudeproduct.

Yield: 18.2 g (48% of theory), R_(f) value: 0.25 (silica gel; methylenechloride/methanol/acetic acid=8:2:0.2)

EXAMPLE II 6-(4-Cyanophenyl)-(2H)-pyridazin-3-one

19.2 g of 3-(4-cyanobenzoyl)-2-hydroxy-propionic acid and 20 ml of 80%hydrazine solution in 200 ml of acetic acid are refluxed for 2 hours.The mixture is left to cool, the precipitate is suction filtered andwashed with acetic acid and ether.

Yield: 10.3 g (60% of theory), R_(f) value: 0.32 (silica gel; methylenechloride/methanol=19:1)

EXAMPLE III 3-Chloro-6-(4-cyanophenyl)-pyridazine

A suspension of 27.6 g of 6-(4-cyanophenyl)-(2H)-pyridazin-3-one in 200ml of phosphorusoxy chloride is refluxed for 2 hours. The reactionsolution is introduced into 1 liter of water, the precipitate is suctionfiltered, washed with water and dried.

Yield: 25.7 g (85% of theory), Melting point: 237°-240° C., R_(f) value:0.75 (silica gel; methylene chloride/methanol=19:1)

The following compound is obtained analogously:

(1) 3-chloro-6-(4-cyanophenyl)-4-(ethoxycarbonyl)-pyridazine

After the reaction solution has been stirred into water the aqueousphase is extracted with ethyl acetate. The organic phase is dried,evaporated down and the residue is chromatographed.

R_(f) value: 0.37 (silica gel; cyclohexane/ethyl acetate=2:1)

EXAMPLE IV Diethyl 2-(4-bromophenyl)-2-oxo-ethylmalonate

124 g of potassium tert.butoxide are added to a solution of 165 ml ofdiethylmalonate in 600 ml of dimethylformamide. Whilst cooling in awater bath 307 g of 4-bromophenacylbromide are added in batcheswhereupon the reaction solution heats up to about 70° C. It is stirredfor 2 hours at ambient temperature, the reaction solution is poured intodilute saline solution and extracted with ethyl acetate. The organicphase is washed with water, dried over sodium sulphate and filtered overactive charcoal. After the solvent has been removed using a rotaryevaporator 398 g of a red oil are obtained which is further reactedwithout being purified.

R_(f) value: 0.40 (silica gel; cyclohexane/ethyl acetate=5:1)

EXAMPLE V6-(4-Bromophenyl)-4,5-dihydro-4-ethoxycarbonyl-(2H)-pyridazin-3-one

To a solution of 398 g of diethyl 2-(4-bromophenyl)-2-oxo-ethylmalonatein 1.5 liters of glacial acetic acid are added 240 ml of 80% hydrazinesolution and the mixture is refluxed for 2 hours. As the reactionsolution cools a precipitate is formed which is suction filtered, washedwith water and dried. In order to isolate further product, the motherliquor is mixed with water, the precipitate is suction filtered andrecrystallised from glacial acetic acid.

Yield: 213 g (61% of theory), R_(f) value: 0.31 (silica gel;cyclohexane/ethyl acetate=2:1)

EXAMPLE VI 6-(4-Bromophenyl)-4-ethoxycarbonyl-(2H)-pyridazin-3-one

To a suspension of 213 g of6-(4-bromophenyl)-4,5-dihydro-4-ethoxycarbonyl-(2H)-pyridazin-3-one in2.0 liters of glacial acetic acid is added dropwise a solution of 40 mlof bromine in 100 ml of glacial acetic acid and the mixture is stirredfor 45 minutes at ambient temperature. It is diluted with 2.0 liters ofwater and excess bromine is destroyed with dilute sodium sulphitesolution. The precipitate is suction filtered, washed with water anddried.

Yield: 206 g (97% of theory), R_(f) value: 0.39 (silica gel; methylenechloride/methanol=15:1)

EXAMPLE VII 6-(4-Cyanophenyl)-4-ethoxycarbonyl-(2H)-pyridazin-3-one

To a solution of 24.6 g of6-(4-bromophenyl)-4-ethoxycarbonyl-(2H)-pyridazin-3-one in 100 ml ofdimethylformamide are added 6.9 g of copper(I)cyanide and the mixture isrefluxed for 6 hours. The reaction solution is cooled and stirred intowater. The precipitate is suction filtered and dried. 23 g of crudeproduct are obtained which is further reacted without purification.

R_(f) value: 0.39 (silica gel; methylene chloride/methanol=15:1)

EXAMPLE VIII6-(4-Cyanophenyl)-4-ethoxycarbonyl-2-methyl-(2H)-pyridazin-3-one

A suspension of 18 g of crude6-(4-cyanophenyl)-4-ethoxycarbonyl-(2H)-pyridazin-3-one, 7.5 ml ofmethyliodide, 2.0 g of methyltrioctylammonium chloride in 200 ml of 2Mpotassium hydrogen carbonate solution, 500 ml of tetrahydrofuran and 1.6liters of toluene is stirred for 16 hours at ambient temperature. 3 mlof methyliodide are added and the mixture is stirred for a further 4hours. The precipitate is suction filtered and the filtrate is washedwith water. The organic phase is dried over sodium sulphate, the solventis evaporated off in vacuo and the crude product is chromatographed oversilica gel.

Yield: 11.2 g (59% of theory), R_(f) value: 0.49 (silica gel; methylenechloride/methanol=9:1)

The following compounds are obtained analogously:

(1) 2-benzyl-6-(4-cyanophenyl)-4-ethoxycarbonyl-(2H)-pyridazin-3-one

Benzylbromide is used.

Melting point: 151°-153° C. R_(f) value: 0.55 (silica gel; methylenechloride/methanol=9:1)

(2)6-(4-cyanophenyl)-4-ethoxycarbonyl-2-[(morpholinocarbonyl)methyl]-(2H)-pyridazin-3-one

1-chloroacetic acid morpholide is used.

Melting point: 186°-192° C. R_(f) value: 0.57 (silica gel; methylenechloride/methanol=9:1)

EXAMPLE IX 4-Carboxy-6-(4-cyanophenyl)-2-methyl-(2H)-pyridazin-3-one

To a solution of 12.0 g of6-(4-cyanophenyl)-4-ethoxycarbonyl-2-methyl-(2H)-pyridazin-3-one in 200ml of tetrahydrofuran is added a solution of 7.14 g of lithium hydroxidemonohydrate in 170 ml of water and the reaction is monitored by thinlayer chromatography. After 11/2 hours the mixture is acidified with 1Nhydrochloric acid, the tetrahydrofuran is evaporated off in vacuo, theresidue is suction filtered and dried.

Yield: 11.2 g (quant.), Melting point: 190°-194° C. R_(f) value: 0.33(silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

The following compounds are obtained analogously:

(1) 4-carboxy-6-(4-cyanophenyl)-(2H)-pyridazin-3-one

Melting point: over 290° C.

(2) 2-(4-carbamoyl-phenyl)-5-carboxy-(3H)-pyrimidin-4-one

R_(f) value: 0.06 (silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

    ______________________________________                                        Calculated:  C 55.60 H 3.50    N 16.21                                        Found:       55.45   3.53      16.36                                          ______________________________________                                    

(3)4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-6-(4-cyanophenyl)-2-methyl-(2H)-pyridazin-3-one

Melting point: 283°-286° C. R_(f) value: 0.39 (silica gel; methylenechloride/methanol/=9:1)

(4) 4-carboxy-3-chloro-6-(4-cyanophenyl)-pyridazine

Melting point: 208°-210° C. (decomp.) R_(f) value: 0.74 (silica gel;methylene chloride/methanol/conc. ammonia solution=4:1:0.25)

(5) 2-benzyl-4-carboxy-6-(4-cyanophenyl)-(2H)-pyridazin-3-one

Melting point: 254°-256° C. R_(f) value: 0.29 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(6)4-carboxy-6-(4-cyanophenyl)-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

Melting point: sintering from 215° C. R_(f) value: 0.16 (silica gel;methylene chloride/methanol/conc. ammonia solution=4:1:0.25)

(7)2-benzyl-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-6-(4-cyanophenyl)-(2H)-pyridazin-3-one

Melting point: 215°-218° C. R_(f) value: 0.51 (silica gel; methylenechloride/methanol=9:1)

EXAMPLE X6-(4-Cyanophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

A solution of 2.0 g of4-carboxy-6-(4-cyanophenyl)-2-methyl-(2H)-pyridazin-3-one and 1.2 g ofN-methylmorpholine in 160 ml of absolute tetrahydrofuran is cooled to-20° C. and mixed with 1.1 g of isobutyl-chloroformate. The mixture isstirred for one hour at -20° C., then cooled to -40° C. and a solutionof 1.57 g of methyl trans-4-amino-cyclohexanecarboxylate in 20 ml ofabsolute tetrahydrofuran is added. The cooling bath is taken away andthe mixture is stirred for 3 hours at ambient temperature. The reactionsolution is poured into 400 ml of 0.1N hydrochloric acid and the aqueousphase is extracted several times with ethyl acetate. Drying the organicphase over sodium sulphate and evaporating off the solvent yields ayellowish solid which is triturated with methanol. It is suctionfiltered and dried and 2.5 g (81% of theory) of product are obtained.

Melting point: 210°-215° C., R_(f) value: 0.85 (silica gel; methylenechloride/methanol=9:1)

The following compounds are obtained analogously:

(1)6-(4-cyanophenyl)-4-[[2-(ethoxycarbonyl)-ethyl]aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

β-alanine-ethylester-hydrochloride is used with one equivalent ofN-methylmorpholine.

Melting point: 132°-136° C., R_(f) value: 0.39 (silica gel; methylenechloride/methanol=20:1)

(2)6-(4-cyanophenyl)-4-[[3-(methoxycarbonyl)-propyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-oneEthyl 4-aminobutyrate-hydrochloride is used with one equivalent ofN-methylmorpholine.

Melting point: 130°-132° C., R_(f) value: 0.42 (silica gel; methylenechloride/methanol=15:)

(3)6-(4-cyanophenyl)-4-[[4-[(methoxycarbonyl)-methyl]-phenyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-oneFreshly distilled methyl 4-aminophenyl-acetate is used.

Melting point: 235°-238° C.,

(4)6-(4-cyanophenyl)-4-[[cis-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Melting point: 190°-192° C., R_(f) value: 0.77 (silica gel; methylenechloride/methanol=15:1)

(5)6-(4-cyanophenyl)-4-[[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-oneMethyl trans-4-(methylamino)-cyclohexane-carboxylate is used.

Melting point: 228°-230° C., R_(f) value: 0.48 (silica gel; methylenechloride/methanol=9:1)

(6)3-chloro-6-(4-cyanophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazine

Melting point (after chromatography): 232°-234° C., R_(f) value: 0.24(silica gel; methylene chloride/methanol=20:1)

(7)2-benzyl-6-(4-cyanophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(2H)-pyridazin-3-one

Melting point: 217°-220° C., R_(f) value: 0.64 (silica gel; methylenechloride/methanol=9:1)

EXAMPLE XI6-(4-Cyanophenyl)-4-[(4-carboxybutyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

A solution of 530 mg of4-carboxy-6-(4-cyanophenyl)-2-methyl(2H)-pyridazin-3-one and 242 mg ofN-methylmorpholine in 20 ml of absolute tetrahydrofuran is cooled to-15° C. and mixed with 273 mg of isobutylchloro-formate. The mixture isstirred for one hour at -15° C. Then a solution of 234 mg of5-amino-valeric acid, 455 mg of N-methylmorpholine and 435 mg oftrimethylsilylchloride in 50 ml of tetrahydrofuran stirred for 16 hoursat ambient temperature is added. After 2 hours the cooling bath isremoved and the mixture is stirred for 3 hours at ambient temperature.The reaction solution is poured into saturated sodium chloride solution,acidified with 2N hydrochloric acid and the aqueous phase is extractedseveral times with ethyl acetate. Drying the organic phase over sodiumsulphate and evaporating off the solvent yields a yellowish solid whichis triturated with a little methylene chloride. The mixture is suctionfiltered and dried and 600 mg (85% of theory) of the product areobtained.

Melting point: 194°-197° C., R_(f) value: 0.51 (silica gel; methylenechloride/methanol=9:1)

The following compound is obtained analogously:

(1) 6-(4-cyanophenyl)-4-[(4-carboxybutyl)-aminocarbonyl]-(2H)-pyridazin-3-one R_(f) value: 0.30 (silica gel;methylene chloride/methanol=9:1)

EXAMPLE XII 4-Amidino-benzoic acid amide-hydrochloride

Dry HCl gas is passed for 2 hours through a solution of 17.5 g of4-cyano-benzoic acid amide in 700 ml of methanol cooled in an ice/waterbath (washing bottle containing concentrated sulphuric acid provided infront). The solution is stirred at ambient temperature and theconversion is monitored by thin layer chromatography. After the reactionis complete the reaction solution is evaporated down at a bathtemperature of 25° to 35° C. in a rotary evaporator, the residue isdissolved in 300 ml of methanol and the solution is mixed with 10.0 g ofammonium carbonate with thorough stirring. The mixture is stirred for 16hours at ambient temperature, the precipitate is removed by suctionfiltering, washed with a little water and dried in vacuo.

Yield: 8.5 g (35% of theory). By concentrating the filtrate andtriturating the residue with a little water, suction filtering anddrying, a further 8.8 g (37% of theory) of product can be obtained.Melting point: over 280° C., R_(f) value: 0.09 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

EXAMPLE XIII2-(4-Carbamoyl-phenyl)-5-ethoxycarbonyl-(3H)-pyrimidin-4-one

Under an inert gas atmosphere a solution of 1.8 g of sodium in 800 ml ofabsolute ethanol is prepared. At 0° C. 8.3 g of 4-amidino-benzoic acidamide-hydrochloride is added in small amounts. The suspension is stirredat 0° C. for 10 minutes. Then 8.7 g of diethylethoxy-methylene malonateare added. The mixture is stirred for 30 minutes at ambient temperatureand refluxed for 2 hours. After a further 16 hours stirring at ambienttemperature the precipitate is suction filtered and washed with ethanol.The residue is triturated with water, suction filtered again and dried.

Yield: 10.15 g (88% of theory), R_(f) value: 0.78 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

EXAMPLE XIV 1:1 Mixture of5-carboxy-4-chloro-2-(4-cyanophenyl)-pyrimidine and4-chloro-5-chloroformyl-2-(4-cyanophenyl)-pyrimidine

A solution of 12.6 g of2-(4-carbamoyl-phenyl)-5-carboxy-(3H)-pyrimidin-4-one in 100 ml ofphosphorus-oxychloride is refluxed for 4 hours. The mixture is left tocool and the reaction solution is poured in small amounts onto waterwhilst the temperature is maintained at between 60°-90° C. by theaddition of ice. The precipitate is suction filtered and dried. 10.3 gof a 1:1 mixture of carboxylic acid and acid chloride is obtained whichis further reacted as it is in Example XV.

EXAMPLE XV4-Chloro-2-(4-cyanophenyl)-5-[4-[(methoxycarbonyl)-methyl]piperidinocarbonyl]-pyrimidine

A solution of 7.0 g of the 1:1 mixture of5-carboxy-4-chloro-2-(4-cyanophenyl)-pyrimidine and4-chloro-5-chloroformyl-2-(4-cyanophenyl)-pyrimidine (from Example XIV)in 60 ml of thionylchloride is refluxed for 3 hours. Excessthionylchloride is evaporated off, the residue is dissolved in drytetrahydrofuran and evaporated down again. It is dissolved in 200 ml ofdry tetrahydrofuran and 4.45 g of methyl piperidine-4-acetatehydrochloride are added. Then a solution of 10.5 ml of triethylamine in25 ml of tetrahydrofuran is added dropwise whilst cooling in anice/water bath and the mixture is stirred for 16 hours at ambienttemperature. The suspension is acidified with 1N hydrochloric acid andthe aqueous phase is extracted with ethyl acetate. The organic phase isevaporated down and the residue is purified by chromatography.

Yield: 5.95 g (65% of theory), R_(f) value: 0.56 (silica gel; methylenechloride/methanol=15:1)

EXAMPLE XVI2-(4-Cyanophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-(3H)-pyrimidin-4-one

A solution of 2.0 g of4-chloro-2-(4-cyanophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidineand 4.1 g of sodium acetate in 150 ml of glacial acetic acid is refluxedfor 24 hours. The glacial acetic acid is evaporated off and the residueis triturated with 200 ml of water. The precipitate is suction filteredand the solid is purified by chromatography over silica gel.

Yield: 0.85 g (45% of theory), R_(f) value: 0.40 (silica gel; methylenechloride/methanol=15:1)

EXAMPLE XVII2-(4-Cyanophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine

1.0 g of 5% palladium on calcium carbonate in 100 ml of dry methanol isprehydrogenated. 1.5 g of4-chloro-2-(4-cyanophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidineand 0.28 g of calcium hydroxide are added and the mixture ishydrogenated for 1.5 hours at ambient temperature and atmosphericpressure. The insoluble components are filtered off, the filtrate isevaporated down and the residue is chromatographed over silica gel.

Yield: 650 mg (47% of theory), R_(f) value: 0.46 (silica gel; ethylacetate/cyclohexane=2:1)

The following compound is obtained analogously:

(1)3-(4-cyanophenyl)-5-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazineR_(f) value: 0.34 (silica gel; ethyl acetate/cyclohexane=2:1)

EXAMPLE XVIII 6-(4-Cyanophenyl)-3-[3-[(ethoxycarbonyl)-methyloxy]-piperidino]-pyridazine

A suspension of 1.50 g of 3-chloro-6-(4-cyanophenyl)-pyridazine, 1.90 gof 3-[(ethoxycarbonyl)-methyloxy]-piperidine and 1.70 g of potassiumcarbonate in 4 ml of dimethylsulphoxide is stirred for one hour at 130°C. The suspension is poured into water and the aqueous phase isextracted three times with ethyl acetate. Drying the ethyl acetate phaseover sodium sulphate and evaporating off the solvent yields an oil whichis chromatographed over silica gel.

Yield: 1.70 g (68% of theory) colourless oil, R_(f) value: 0.42 (silicagel; cyclohexane/ethyl acetate=2:3)

The following compounds are obtained analogously:

(1)6-(4-cyanophenyl)-3-[[trans-4-(methoxycarbonyl)-cyclohexyl]-amino]-pyridazine

R_(f) value: 0.20 (silica gel; methylene chloride/methanol=100:1)

(2)6-(4-cyanophenyl)-3-[[3-(methoxycarbonyl)-phenyl]-methylamino]-pyridazine

R_(f) value: 0.48 (silica gel; methylene chloride/methanol=40:1)

(3)6-(4-cyanophenyl)-3-[4-[2-(methoxycarbonyl)-ethyl]-phenyloxy]-pyridazine

The mixture is heated to 80°-90° C. for 2.5 hours.

Melting point: 164°-167° C., R_(f) value: 0.19 (silica gel; methylenechloride/methanol=100:1)

(4)6-(4-cyanophenyl)-3-[4-[(methoxycarbonyl)-methyloxy]-phenyloxy]-pyridazine

The mixture is heated to 80°-90° C. for 2.5 hours. The crude product istriturated with ethyl acetate and the precipitate is suction filteredand dried.

R_(f) value: 0.45 (silica gel; methylene chloride/methanol=20:1)

(5)6-(4-cyanophenyl)-3-[[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl]-amino]-pyridazine

R_(f) value: 0.21 (silica gel; methylene chloride/methanol=30:1)

EXAMPLE XIX6-(4-Cyanophenyl)-3-[4-[2-(methoxycarbonyl)-ethyl]-phenylamino]-pyridazine

0.60 g of 3-chloro-6-(4-cyanophenyl)-pyridazine are heated to 140°-150°C. for 1.5 hours with 1.70 g of 4-[2-(methoxycarbonyl)ethyl]-aniline.The cooled melt is dissolved in methylene chloride and the organic phaseis extracted with 1N sodium hydroxide solution. Drying the organic phaseover sodium sulphate and evaporating off the solvent yields a solidwhich is chromatographed over silica gel.

Yield: 1.80 g (95% of theory), Melting point: 212°-217° C., R_(f) value:0.34 (silica gel; methylene chloride/methanol=20:1)

EXAMPLE XX6-(4-Cyanophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-3-morpholino-pyridazine

A solution of 1.0 g of3-chloro-6-(4-cyanophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazinein 10 ml of morpholine is refluxed for 2 hours. Excess morpholine isevaporated off, the residue is mixed with 0.5 N sodium hydroxidesolution and the aqueous phase is extracted with methylene chloride. Theorganic phase is dried over sodium sulphate and evaporated down. 1.1 gof crude product are obtained which is chromatographed over silica gel.

Yield: 650 mg (49% of theory), Melting point: 269°-271° C., R_(f) value:0.29 (silica gel; methylene chloride/methanol=20:1)

EXAMPLE XXI Cis- and trans methyl4-(N,N-dibenzylamino)-cyclohexylcarboxylate

A solution of 68.0 g of a cis/trans mixture of methyl4-aminocyclohexyl-carboxylate, 154 g of benzylbromide and 156 g ofN-ethyl-diisopropylamine in 300 ml of methanol are refluxed for 2 hours.The reaction solution is evaporated down. To the residue is added waterfollowed by sufficient 1N sodium hydroxide solution to render thesuspension alkaline. It is extracted several times with ethyl acetate,the organic phase is dried over sodium sulphate and the solvent isevaporated off. 130 g of an oil are obtained which is chromatographedwith cyclohexane/ethyl acetate in the ratio 16:1 over silica gel.

Yield: 54 g of cis methyl 4-(N,N-dibenzylamino)-cyclohexyl-carboxylate(46% of theory), Melting point: 114°-116° C. R_(f) value: 0.61 (silicagel; cyclohexane/ethyl acetate=4:1)

Yield: 25.5 g of trans methyl4-(N,N-dibenzylamino)-cyclohexyl-carboxylate (22% of theory), Meltingpoint: 71°-74° C. R_(f) value: 0.56 (silica gel; cyclohexane/ethylacetate=4:1)

The following compounds are obtained analogously:

(1) cis- and trans methyl4-(N-benzyl-methylamino)-cyclohexyl-carboxylate

The crude product is chromatographed with cyclohexane/ethyl acetate inthe ratio 20:1 over aluminium oxide of activity stage III.

cis methyl 4-(N-benzyl-methylamino)-cyclohexyl-carboxylate R_(f) value:0.35 (aluminium oxide; cyclohexane/ethyl acetate=10:1)

trans methyl 4-(N-benzyl-methylamino)-cyclohexyl-carboxylate R_(f)value: 0.27 (aluminium oxide; cyclohexane/ethyl acetate=10:1)

EXAMPLE XXII Trans methyl 4-aminocyclohexyl-carboxylate

A suspension of 25 g of trans methyl4-(N,N-dibenzylamino)-cyclohexyl-carboxylate and 5.0 g of 10% palladiumon charcoal in 500 ml of methanol is hydrogenated for one hour at 40° C.under a hydrogen pressure of 3.6 bar. The catalyst is filtered off andthe filtrate is evaporated down.

Yield: 11.0 g oil (95% of theory), R_(f) value: 0.69 (silica gel;methylene chloride/methanol/conc. ammonia solution=4:1:0.25)

The following compounds are obtained analogously:

(1) cis methyl 4-aminocyclohexyl-carboxylate

R_(f) value: 0.69 (silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(2) trans methyl 4-(methylamino)-cyclohexyl-carboxylate

R_(f) value: 0.75 (silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

EXAMPLE XXIII6-(4-Cyanophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

A suspension of 1.2 g of4-carboxy-6-(4-cyanophenyl)-2-[(morpholinocarbonyl)methyl]-(2H)-pyridazin-3-one1.29 g of2-[(1H)-benzotriazol-1-yl]-1,1,3,3-tetramethyl-uroniumtetrafluoroborate,0.64 g of trans methyl-4-aminocyclohexanecarboxylate-hydrochloride, 0.54g of 1-hydroxy-(1H)-benzotriazole hydrate and 0.81 g ofN-methylmorpholine in 100 ml of dimethylformamide is stirred for 16hours at ambient temperature. The solvent is evaporated off underreduced pressure at a bath temperature of 80° C. and the remaining oilis chromatographed.

Yield: 1.38 g (83% of theory), Melting point: 195°-200° C. R_(f) value:0.63 (silica gel; methylene chloride/methanol=9:1)

Preparation of the End Compounds EXAMPLE 16-(4-Amidinophenyl)-4-[(4-carboxybutyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

A solution of 300 mg of6-[4-amidinophenyl)-4-[[4-(methoxycarbonyl)-butyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-oneand 125 mg of lithium hydroxide-monohydrate in a mixture of 20 ml oftetrohydrofuran and 16 ml of water is stirred for 11/2 hours at ambienttemperature. Then 1.0 g of ammonium chloride is added and the mixture isstirred for 20 minutes. Excess tetrahydrofuran is suction filtered,washed with water and acetone and dried.

Yield: 250 mg 191% of theory), Melting point: over 250° C., Massspectrum: 372 (M+1)⁺ R_(f) value: 0.24 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

The following compounds are obtained analogously:

(1)6-(4-amidinophenyl)-4-[(3-carboxypropyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

1N sodium hydroxide solution in methanol is used.

Melting point: from 280° C. (decomp.), Mass spectrum: 358 (M+1)⁺ R_(f)value: 0.26 (silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(2)6-(4-amidinophenyl)-4-[(2-carboxyethyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Melting point: from 265° C. (decomp.), Mass spectrum: (M+1)⁺ R_(f)value: 0.19 (silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

    ______________________________________                                        Calculated:  C 50.66 H 5.58    N 18.64                                        Found:       50.78   5.63      18.66                                          ______________________________________                                    

(3)6-(4-amidinophenyl)-4-[(4-carboxybutyl)-aminocarbonyl]-2H-pyridazin-3-one

Mass spectrum: 358 (M+1)⁺ R_(f) value: 0.27 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(4)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Melting point: 263°-266° C., Mass spectrum: 398 (M+1)⁺ R_(f) value: 0.16(silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

    ______________________________________                                        Calc. × 1 H.sub.2 O:                                                                  C 57.82 H 6.07    N 16.86                                       Found:        57.99   6.08      16.92                                         ______________________________________                                    

(5)6-(4-amidinophenyl)-4-[(cis-4-carboxycyclohexyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Melting point: 266°-269° C., Mass spectrum: 398 (M+1)⁺ R_(f) value: 0.15(silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(6)6-(4-amidinophenyl)-4-[[4-(carboxymethyl)-phenyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

1N sodium hydroxide solution is used and the solvent is a mixture ofmethylene chloride/methanol/tetrahydrofuran in the ratio 1:1:0.6.

Melting point: from 255° C. (decomp.) Mass spectrum: 406 (M+1)⁺

(7) 6-(4-amidinophenyl)-3-[4-(2-carboxyethyl)-phenylamino]-pyridazine

Melting point: above 260° C., R_(f) value: 0.09 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

    ______________________________________                                        Calc. × 0.5 H.sub.2 O:                                                                 C 64.85 H 5.44    N 18.90                                      Found:         64.61   5.64      18.67                                        ______________________________________                                    

(8) 6-(4-amidinophenyl)-3-[4-(2-carboxyethyl)-phenyloxy]-pyridazine

The crude product is chromatographically purified.

Mass spectrum: 363 (M+1)⁺ R_(f) value: 0.12 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(9) 6-(4-amidinophenyl)-3-[(3-carboxyphenyl)-methylamino]-pyridazine

Melting point: over 260° C., Mass spectrum: 348 (M+1)⁺ R_(f) value: 0.22(silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(10)6-(4-amidinophenyl)-3-[3-[(carboxymethyl)-oxy]-piperidino]-pyridazine

Melting point: from 278° C., Mass spectrum: 356 (M+1)⁺ R_(f) value: 0.21(silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(11) 6-(4-amidinophenyl)-3-[(trans-4-carboxycyclohexyl)-amino]-pyridazine

Mass spectrum: 340 (M+1)⁺ R_(f) value: 0.14 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(12) 6-(4-amidinophenyl)-3-[N-(trans-4-carboxycyclohexyl)-N-methylamino]-pyridazine

Melting point: 308°-310° C., Mass spectrum: 368 (M+1)⁺ R_(f) value: 0.25(silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(13)2-(4-amidinophenyl)-5-[4-(carboxymethyl)-piperidinocarbonyl]-(3H)-pyrimidin-4-one

Mass spectrum: 383 M⁺ R_(f) value: 0.09 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

    ______________________________________                                        Calc. × H.sub.2 O:                                                                    56.85   5.78      N 17.45                                       Found:        57.06   5.59      17.15                                         ______________________________________                                    

(14)2-(4-amidinophenyl)-5-[4-(carboxymethyl)-piperidinocarbonyl]-4-methoxy-pyrimidine

Mass spectrum: 398 (M+1)⁺ R_(f) value: 0.38 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(15)2-(4-amidinophenyl)-5-[4-(carboxymethyl)-piperidinocarbonyl]-pyrimidine

Mass spectrum: 368 (M+1)⁺ R_(f) value: 0.20 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(16)6-(4-amidinophenyl)-4-[N-(trans-4-carboxycyclohexyl)-N-methyl-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Mass spectrum: 412 (M+1)⁺ R_(f) value: 0.11 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(17)6-(4-amidinophenyl)-2-(carbamoyl-methyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-(2H)-pyridazin-3-one

(18)6-(4-amidinophenyl)-2-benzyl-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-(2H)-pyridazin-3-one

Mass spectrum: 474 (M+H)⁺ R_(f) value: 0.14 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(19)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-(2H)-pyridazin-3-one

(20)3-(4-amidinophenyl)-5-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-pyridazine

Melting point: 292°-296° C., Mass spectrum: 368 (M+1)⁺ R_(f) value: 0.07(silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(21)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-3-methoxy-pyridazine

Melting point: sintering from 270°-280° C., Mass spectrum: 398 (M+1)⁺R_(f) value: 0.26 (silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(22)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-3-morpholino-pyridazine

Melting point: 265°-270° C., Mass spectrum: 453 (M+1)⁺ R_(f) value: 0.28(silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(23)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-3-ethoxy-pyridazine

(24)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-3-thiomorpholino-pyridazine

(25)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-3-dimethylamino-pyridazine

(26)3-(4-acetyl-piperazino)-6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-pyridazine

(27)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-3-piperidino-pyridazine

(28)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-3-pyrrolidino-pyridazine

(29)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-[(N,N-dimethyl-aminocarbonyl)-methyl]-(2H)-pyridazin-3-one

(30)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one-hydrochloride

Instead of adding ammonium chloride the mixture is acidified with 1Nhydrochloric acid.

Melting point: sintering from 245° C., Mass spectrum: 511 (M+H)⁺ R_(f)value: 0.16 (silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(31)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-ethyl-(2H)-pyridazin-3-one

(32)5-(4-amidinophenyl)-3-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-pyridin-2-one

(33)5-(4-amidinophenyl)-3-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-1-methyl-pyridin-2-one

(34)5-(4-amidinophenyl)-3-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-(1H)-pyrazin-2-one

(35)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-phenyl-(2H)-pyridazin-3-one

(36)6-(4-amidino-2-methyl-phenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

(37)6-(4-amidino-2-fluoro-phenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

(38)3-(4-amidinophenyl)-5-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-(1H)-1,2,4-triazin-6-one

(39)6-(4-amidinophenyl)-4-[[[(carboxymethyl)-aminocarbonyl]-methyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

(40)6-(4-amidinophenyl)-4-[[[N-(carboxymethyl)-N-methyl-aminocarbonyl]-methyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

(41)4-[[2-[N-acetyl-N-(carboxymethyl)-amino]-ethyl]-aminocarbonyl]-6-(4-amidinophenyl)-2-methyl-(2H)-pyridazin-3-one

(42)6-(4-amidinophenyl)-4-[[2-[(carboxymethyl)-oxy]-ethyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

(43)6-(4-amidinophenyl)-4-[[2-[N-(carboxymethyl)-N-(methanesulphonyl)-amino]-ethyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

(44)6-(4-amidinophenyl)-4-[[2-[N-benzyl-N-(carboxymethyl)-amino]-ethyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

(45)6-(4-amidinophenyl)-4-[(3-carboxy-prop-2-enyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

(46)5-(4-amidinophenyl)-2-[4-(carboxymethyl)-piperidinocarbonyl]-pyrimidine

(47)3-amidino-6-[4-[4-(carboxymethyl)-piperidinocarbonyl]-phenyl]-pyridine

(48) 5-(4-amidinophenyl)-2-[(3-carboxypropyl )-aminocarbonyl]-pyrimidine

(49)5-(4-amidinophenyl)-2-[N-(3-carboxypropyl)-N-methylaminocarbonyl]-pyrimidine

(50) 5-(4-amidinophenyl)-2-[(4-carboxybutyl)-aminocarbonyl]-pyrimidine

(51)2-[[2-[N-acetyl-N-(carboxymethyl)-amino]-ethyl]-aminocarbonyl]-5-(4-amidinophenyl)-pyrimidine

(52)5-(4-amidinophenyl)-2-[4-(carboxymethyl)-piperidinocarbonyl]-pyrazine

(53)2-(4-amidinophenyl)-5-[4-(carboxymethyl)-piperidinocarbonyl]-3-methyl-(3H)-pyrimidin-4-one

(54)3-amidino-6-[4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-phenyl]-pyridin

(55)5-(4-amidino-3-fluorophenyl)-2-[4-(carboxymethyl)-piperidinocarbonyl]-pyrimidine

(56)5-(4-amidino-2-chlorophenyl)-2-[4-(carboxymethyl)-piperidinocarbonyl]-pyrimidine

(57)2-(4-amidino-2-methyl-phenyl)-5-[4-(carboxymethyl)-piperidinocarbonyl]-pyrimidine

(58)5-(5-amidinopyridin-2-yl)-2-[4-(carboxymethyl)-piperidinocarbonyl]-pyrimidine

(59)5-(4-amidinophenyl)-2-[4-(carboxymethyl)-piperidinocarbonyl]-pyridine

(60)5-amidino-2-[4-[4-(carboxymethyl)-piperidinocarbonyl]-phenyl]-pyrimidine

(61)5-(4-amidinophenyl)-2-[4-(carboxymethyl)-piperazinocarbonyl]-pyrimidine

(62)5-(4-amidinophenyl)-2-[4-(2-carboxyethyl)-piperazinocarbonyl]-pyrimidine

(63)5-(4-amidinophenyl)-2-[4-(1-carboxyethyl)-piperidinocarbonyl]-pyrimidine

(64)5-(4-amidinophenyl)-2-[4-(carboxymethyl)-3-oxy-piperazinocarbonyl]-pyrimidine

(65)5-(4-amidinophenyl)-2-[3-(carboxymethyl)-piperidinocarbonyl]-pyrimidine

(66)6-(4-amidinophenyl)-3-[3-[(carboxymethyl)-oxy]-pyrrolidino]-pyridazine

(67) 6-(4-amidinophenyl)-3-[3-(2-carboxyethyl)-piperidino]-pyridazine

(68) 6-(4-amidinophenyl)-3-[4-(2-carboxyethyl)-piperidino]-pyridazine

(69) 6-(4-amidinophenyl)-3-[4-(2-carboxyethyl)-piperazino]-pyridazine

(70) 6-(4-amidinophenyl)-3-[4-(carboxymethyl)-piperidino]-pyridazine

(71) 6-(4-amidinophenyl)-3-[4-(carboxymethyl)-piperazino]-pyridazine

(72)6-(4-amidinophenyl)-3-[[4-(carboxymethyl)-cyclohexylamino]-pyridazine

(73)6-(4-amidinophenyl)-3-[N-[4-(carboxymethyl)-cyclohexyl]-N-methyl-amino]-pyridazine

(74)6-(4-amidinophenyl)-3-[N-(4-carboxybutyl)-N-methyl-amino]-pyridazine

(75)6-(4-amidinophenyl)-3-[N-(5-carboxypentyl)-N-methylamino]-pyridazine

(76) 3-amidino-6-[4-[(4-carboxybutyl)-oxy]-phenyl]-pyridine

(77) 2-amidino-5-[4-[(5-carboxypentyl)-oxy]-phenyl]-pyrazine

(78)5-(4-amidinophenyl)-2-[trans-4-(carboxycyclohexyl)-amino]-pyrimidine

(79) 5-(4-amidinophenyl)-2-[trans-4-(carboxycyclohexyl)-amino]-pyridine

(80)5-amidino-2-[4-[[(2-carboxyethyl)-aminocarbonyl]-methyloxy]-phenyl]-pyrimidine

(81)5-amidino-2-[4-[(4-carboxy-piperidinocarbonyl)-methyloxy]-phenyl]-1,3-thiazole

(82)2-amidino-5-[4-[[(carboxymethyl)-aminocarbonyl]-methyloxy]phenyl]-pyrimidine

(83)6-(4-amidinophenyl)-3-amino-4-[N-(trans-4-carboxycyclohexyl)-N-methyl-aminocarbonyl]-pyridazine

(84)6-(4-amidinophenyl)-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-[[(1-carboxy-2-phenyl-ethyl)-aminocarbonyl]-methyl]-(2H)-pyridazin-3-one

(85)6-(4-amidinophenyl)-4-[N-(trans-4-carboxycyclohexyl)-aminocarbonyl]-N-methyl-aminocarbonyl]-2-[[(1-carboxyethyl)-aminocarbonyl]-methyl]-(2H)-pyridazin-3-one

(86)2-[4-[N-[(3-carboxyprop-1-yl)-carbonyl]-N-methyl-amino]-phenyl]-5-(N-methyl-amidino)-pyridine

(87)5-(4-amidinophenyl)-2-[[4-(carboxymethyl)-piperidino]-methyl]-pyrimidine

(88) 5-amidino-2-[4-[(4-carboxybutyl)-aminosulphonyl]-phenyl]-pyrimidine

(89)5-(4-amidinophenyl)-2-[(4-(carboxymethylidene)-piperidinocarbonyl]-pyrimidine

(90)2-(4-amidinophenyl)-5-[4,4-bis-(carboxymethyl)-piperidinocarbonyl]-pyrimidine

(91)1-(4-amidinophenyl)-5-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-(1H)-pyridin-2-one

(92)4-[4-[N-(n-butyl)-amidino]-phenyl]-1-[[(2-carboxyethyl)-aminocarbonyl]-methyl]-(1H)-pyridin-2-one

(93)2-[4-(aminomethyl)-phenyl]-5-[4-(carboxymethyl)-piperidinocarbonyl]-(3H)-pyrimidin-4-one-hydrochloride

Instead of adding ammonium chloride the mixture is acidified with 1Nhydrochloric acid.

Mass spectrum: 371 (M+H)⁺ R_(f) value: 0.01 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(94)6-(4-amidinophenyl)-4-[4-(carboxymethyl)-piperidinocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

(95) 6-(4-amidinophenyl)-4-[N-(trans-4-(carboxy-cyclohexyl)-N-methyl-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

(96)2-(4-amidinophenyl)-5-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-4-methoxy-pyrimidine

(97)2-(4-amidinophenyl)-5-1N-(trans-4-carboxycyclohexyl)-N-methyl-aminocarbonyl]-pyrimidine

(98)2-(4-amidinophenyl)-5-[N-(trans-4-carboxycyclo-hexyl)-N-methyl-aminocarbonyl]-4-ethoxy-pyrimidine

EXAMPLE 26-(4-Amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

2.40 g of6-(4-cyanophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-oneare dissolved in 50 ml of absolute methylene chloride and 500 ml ofabsolute methanol. Whilst cooling in a bath of ice/water, dry HCl gas ispassed through for 2 hours (washing bottle containing concentratedsulphuric acid provided in front). The reaction solution is stirred atambient temperature and the conversion is monitored by thin layerchromatography. After reaction is complete the reaction solution isevaporated down in vacuo at a bath temperature of 25°-35° C., theresidue is dissolved in 300 ml of absolute methanol and 15.0 g ofammonium carbonate are added to the solution which is stirredthoroughly. It is stirred for 16 hours at ambient temperature, theprecipitate is suction filtered and washed with methanol and water.

Yield: 1.2 g (48% of theory), Melting point: 198°-205° C. Mass spectrum:412 (M+1)⁺

By evaporating down the filtrate, triturating the residue with water andsuction filtering, a further 0.75 g of product are obtained.

Melting point: 198°-205° C. R_(f) value: 0.33 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

    ______________________________________                                        Calculated:  C 61.30 C 6.12    N 17.02                                        Found:       61.05   6.31      16.91                                          ______________________________________                                    

The following compounds are obtained analogously:

(1)6-(4-amidinophenyl)-4-[[4-(methoxycarbonyl)-butyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

The starting material used is6-(4-cyanophenyl)-4-[(4-carboxybutyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Mass spectrum: 386 (M+1)⁺ R_(f) value: 0.70 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(2)6-(4-amidinophenyl)-4-[[3-(methoxycarbonyl)-propyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

R_(f) value: 0.31 (silica gel; methylene chloride/methanol/conc. ammoniasolution=2:1:0.25)

(3)6-(4-amidinophenyl)-4-[[2-(methoxycarbonyl)-ethyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

The starting material used is6-(4-cyanophenyl)-4-[[2-ethoxycarbonyl)-ethyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Melting point: 182°-185° C., Mass spectrum: 358 (M+1)⁺ R_(f) value: 0.27(silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(4)6-(4-amidinophenyl)-4-[[4-(methoxycarbonyl)-butyl]-aminocarbonyl]-(2H)-pyridazin-3-one

The starting material used is6-(4-cyanophenyl)-4-[(4-carboxybutyl)-aminocarbonyl]-(2H)-pyridazin-3-one.The crude product is purified by chromatography.

Mass spectrum: 372 (M+1)⁺ R_(f) value: 0.40 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(5)6-(4-amidinophenyl)-4-[[cis-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Mass spectrum: 412 (M+1)⁺ R_(f) value: 0.24 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(6)6-(4-amidinophenyl)-4-[[4-[(methoxycarbonyl)-methyl]-phenyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

Melting point: from 265° C. (decomp.), Mass spectrum: 402 (M+1)⁺ R_(f)value: 0.34 (silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(7)6-(4-amidinophenyl)-3-[4-[2-(methoxycarbonyl)-ethyl]-phenylamino]-pyridazine-hydrochloride

The crude product is purified by chromatography.

Melting point: over 200° C., Mass spectrum: 376 (M+1)⁺ R_(f) value: 0.15(silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

    ______________________________________                                        Calc.: × 1 HCl × 1 H.sub.2 O:                                                    C 58.67 H 5.63  N 16.29                                                                              Cl 8.25                                 Found:         58.82   5.74    16.45  8.04                                    ______________________________________                                    

(8)6-(4-amidinophenyl)-3-[4-[2-(methoxycarbonyl)-ethyl]-phenyloxy]-pyridazine

The crude product is purified by chromatography.

Melting point: 178°-181° C., Mass spectrum: 377 (M+1)⁺ R_(f) value: 0.40(silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

    ______________________________________                                        Calculated:  C 67.01 H 5.36    N 14.88                                        Found:       66.72   5.31      14.61                                          ______________________________________                                    

(9)6-(4-amidinophenyl)-3-[4-[(methoxycarbonyl)-methyloxy]-phenyloxy]-pyridazineand 6-(4-amidinophenyl)-3-[4-(carboxymethyloxy)-phenyloxy]-pyridazine

The crude product is chromatographed. A mixture of the methylester andthe free acid is obtained. By triturating the mixture with methylenechloride/methanol (1:1) and suction filtering the precipitate the freeacid can be concentrated.

R_(f) value (methylester): 0.58 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

R_(f) value (acid): 0.44 (silica gel; methylene chloride/methanol/conc.ammonia solution 2:1:0.25)

Mass spectrum (acid): 365 (M+1)⁺

(10)6-(4-amidinophenyl)-3-[[3-(methoxycarbonyl)-phenyl]-methylamino]-pyridazine-hydrochloride

The reaction is carried out in methanol. The crude product is purifiedby chromatography.

Mass spectrum: 362 (M+1)⁺ R_(f) value: 0.34 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(11)6-(4-amidinophenyl)-3-[3-[(methoxycarbonyl)-methyloxy]-piperidino]-pyridazine-hydrochloride

The starting product used is6-(4-cyanophenyl)-3-[3-[(ethoxycarbonyl)-methyloxy]-piperidino]-pyridazine.The reaction is carried out in methanol.

R_(f) value: 0.23 (silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(12)6-(4-amidinophenyl)-3-[[trans-4-(methoxycarbonyl)-cyclohexyl]-amino]-pyridazine

The reaction is carried out in methanol. The crude product is purifiedby chromatography.

Mass spectrum: 354 (M+1)⁺ R_(f) value: 0.28 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(13)6-(4-amidinophenyl)-3-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-amino]-pyridazine-hydrochloride

The reaction is carried out in methanol. The crude product is purifiedby chromatography.

Melting point: sintering from 155° C., Mass spectrum: 368 (M+1)⁺ R_(f)value: 0.21 (silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(14)2-(4-amidinophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-(3H)-pyrimidin-4-one-hydrochloride

The reaction is carried out in methanol. The crude product is purifiedby chromatography.

Mass spectrum: 398 (M+1)⁺ R_(f) value: 0.13 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(15)2-(4-amidinophenyl)-4-methoxy-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

The starting material used is4-chloro-2-(4-cyanophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine.The reaction is carried out in methanol. The crude product is purifiedby chromatography.

Mass spectrum: 412 (M+H)⁺ R_(f) value: 0.07 (silica gel; methylenechloride/methanol=6:1)

(16)2-(4-amidinophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

The reaction is carried out in methanol. The crude product is purifiedby chromatography.

Mass spectrum: 382 (M+H)⁺ R_(f) value: 0.29 (silica gel; methylenechloride/methanol=4:1)

(17)6-(4-amidinophenyl)-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

Melting point: sintering 200°-215° C., Mass spectrum: 426 (M+H)⁺ R_(f)value: 0.52 (silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(18)6-(4-amidinophenyl)-2-(carbamoyl-methyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

(19)6-(4-amidinophenyl)-2-benzyl-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(2H)-pyridazin-3-one

The reaction is carried out in methanol. The crude product is purifiedby chromatography.

Melting point: 168°-173° C., Mass spectrum: 488 (M+H)⁺ R_(f) value: 0.27(silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(20)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

(21)3-(4-amidinophenyl)-5-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazine-hydrochloride

Melting point: 275°-280° C., Mass spectrum: 382 (M+1)⁺ R_(f) value: 0.18(silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(22)6-(4-amidinophenyl)-3-methoxy-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazine-hydrochloride

Mass spectrum: 412 (M+1)⁺ R_(f) value: 0.29 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

(23)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-3-morpholino-pyridazine-hydrochloride

Melting point: from 290° C. (decomp.), Mass spectrum: 467 (M+1)⁺ R_(f)value: 0.16 (silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

(24)6-(4-amidinophenyl)-2-ethoxy-4-[[trans-4-(ethoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazine-hydrochloride

The reaction is carried out in absolute ethanol.

(25)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-3-thiomorpholino-pyridazine-hydrochloride

(26)6-(4-amidinophenyl)-3-dimethylamino-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazine-hydrochloride

(27)3-(4-acetyl-piperazino)-6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyridazine-hydrochloride

(28)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-3-piperidino-pyridazine-hydrochloride

(29)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-3-pyrrolidino-pyridazine-hydrochloride

(30)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[(N,N-dimethyl-aminocarbonyl)-methyl]-(2H)-pyridazin-3-one-hydrochloride

(31)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

The reaction is carried out in methanol. The crude product is purifiedby chromatography.

Mass spectrum: 524 M⁺ R_(f) value: 0.22 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(32)6-(4-amidinophenyl)-2-ethyl-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

(33)5-(4-amidinophenyl)-3-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(1H)-pyridin-2-one-hydrochloride

(34)5-(4-amidinophenyl)-3-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-1-methyl-(1H)-pyridin-2-one-hydrochloride

(35)5-(4-amidinophenyl)-3-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(1H)-pyrazin-2-one-hydrochloride

(36)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-phenyl-(2H)-pyridazin-3-one-hydrochloride

(37)6-(4-amidino-2-methyl-phenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

(38)6-(4-amidino-2-fluoro-phenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

(39)3-(4-amidino-5-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(1H)-1,2,4-triazin-6-one-hydrochloride

(40)6-(4-amidinophenyl)-4-[[[[(methoxycarbonyl)-methyl]-aminocarbonyl]-methyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

(41)6-(4-amidinophenyl)-4-[[[N-[(methoxycarbonyl)-methyl]-N-methyl-aminocarbonyl]-methyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

(42)4-[[[N-acetyl-N-[(methoxycarbonyl)-methyl]-aminocarbonyl]-methyl]-aminocarbonyl]-6-(4-amidinophenyl)-2-methyl-(2H)-pyridazin-2-one-hydrochloride

(43)6-(4-amidinophenyl)-4-[[2-[[(methoxycarbonyl)-methyl]-oxy]-ethyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

(44)6-(4-amidinophenyl)-4-[[2-[N-(methanesulphonyl)-N-[(methoxycarbonyl)-methyl]-amino]-ethyl]-aminocarbonyl]-2-methyl]-(2H)-pyridazin-3-one-hydrochlorid

(45)6-(4-amidinophenyl)-4-[[2-[N-benzoyl-N-[(methoxycarbonyl)-methyl]-amino]-ethyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

(46) 6-(4-amidinophenyl)-2-methyl-4-[[3-(tetrazol-5-yl)-propyl]-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

(47)6-(4-amidinophenyl)-2-methyl-4-[[4-(tetrazol-5-yl)-butyl]-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

(48)6-(4-amidinophenyl)-2-methyl-4-[(3-phosphono-propyl)-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

(49)6-(4-amidinophenyl)-2-methyl-4-[[4-(O-methyl-phosphono)-butyl]-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

(50)6-(4-amidinophenyl)-2-methyl-4-[(4-sulphobutyl)-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

(51)5-(4-amidinophenyl)-2-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

(52)3-amidino-6-[4-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-phenyl]-pyridine-hydrochloride

(53)5-(4-amidinophenyl)-2-[[3-(methoxycarbonyl)-propyl]-aminocarbonyl]-pyrimidine-hydrochloride

(54)5-(4-amidinophenyl)-2-[N-[3-(methoxycarbonyl)-propyl]-N-methyl-aminocarbonyl]-pyrimidine-hydrochloride

(55)5-(4-amidinophenyl)-2-[[4-(methoxycarbonyl)-butyl]-aminocarbonyl]-pyrimidine-hydrochloride

(56)2-[[2-[N-acetyl-N-[(methoxycarbonyl)-methyl]-amino]-ethyl]-aminocarbonyl]-5-(4-amidinophenyl)-pyrimidine-hydrochloride

(57)5-(4-amidinophenyl)-2-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrazine-hydrochloride

(58)2-(4-amidinophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-3-methyl-(3H)-pyrimidin-4-one-hydrochloride

(59)3-amidino-6-[4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-phenyl]-pyridine-hydrochloride

(60)5-(4-amidino-3-fluorophenyl)-2-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

(61)5-(4-amidino-2-chlorophenyl)-2-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

(62)5-(4-amidino-2-methyl-phenyl)-2-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

(63) 5-(5-amidinopyridin-2-yl)-2-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

(64)5-(4-amidinophenyl)-2-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyridine-hydrochloride

(65)5-amidino-2-[4-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-phenyl]-pyrimidine-hydrochloride

(66)5-(4-amidinophenyl)-2-[4-[(methoxycarbonyl)-methyl]-piperazinocarbonyl]-pyrimidine-hydrochloride

(67)5-(4-amidinophenyl)-2-[4-[2-(methoxycarbonyl)-ethyl]-piperazinocarbonyl]-pyrimidine-hydrochloride

(68)5-(4-amidinophenyl)-2-[4-[1-(methoxycarbonyl)-ethyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

(69)5-(4-amidinophenyl)-2-[4-[(methoxycarbonyl)-methyl]-3-oxy-piperazinocarbonyl]-pyrimidine-hydrochloride

(70)5-(4-amidinophenyl)-2-[3-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

(71)6-(4-amidinophenyl)-3-[3-[[(methoxycarbonyl)-methyl]-oxy]-pyrrolidino]-pyridazine-hydrochloride

(72)6-(4-amidinophenyl)-3-[3-[2-(methoxycarbonyl)-ethyl]-piperidino]-pyridazine-hydrochloride

(73)6-(4-amidinophenyl)-3-[4-[2-(methoxycarbonyl)-ethyl]-piperidino]-pyridazine-hydrochloride

(74)6-(4-amidinophenyl)-3-[4-[2-(methoxycarbonyl)-ethyl]-piperazino]-pyridazine-hydrochloride

(75)6-(4-amidinophenyl)-3-[4-[(methoxycarbonyl)-methyl]-piperidino]-pyridazine-hydrochloride

(76)6-(4-amidinophenyl)-3-[4-[(methoxycarbonyl)-methyl]-piperazino]-pyridazine-hydrochloride

(77)6-(4-amidinophenyl)-3-[[4-[(methoxycarbonyl)-methyl]-cyclohexyl]-amino]-pyridazine-hydrochloride

(78)6-(4-amidinophenyl)-3-[N-[4-[(methoxycarbonyl)-methyl]-cyclohexyl]-N-methyl-amino]-pyridazine-hydrochloride

(79)6-(4-amidinophenyl)-3-[N-[4-[(methoxycarbonyl)-butyl]-N-methyl-amino]-pyridazine-hydrochloride

(80)6-(4-amidinophenyl)-3-[N-[5-(methoxycarbonyl)-pentyl]-N-methyl-amino]-pyridazine-hydrochloride

(81)3-amidino-5-[4-[[4-(methoxycarbonyl)-butyl]-oxy]-phenyl]-pyridine-hydrochloride

(82)2-amidino-5-[4-[[5-(methoxycarbonyl)-pentyl]-oxy]-phenyl]-pyrazine-hydrochloride

(83)5-(4-amidinophenyl)-2-[[trans-4-(methoxycarbonyl)-cyclohexyl]-amino]-pyrimidine-hydrochloride

(84)5-(4-amidinophenyl)-2-[[trans-4-(methoxycarbonyl)-cyclohexyl]-amino]-pyridine-hydrochloride

(85)5-amidino-2-[4-[[[2-(methoxycarbonyl)-ethyl]-aminocarbonyl]-methyloxy]-phenyl]-pyrimidine-hydrochloride

(86)5-amidino-2-[4-[[4-(methoxycarbonyl)-piperidinocarbonyl]-methyloxy]-phenyl]-1,3-thiazole-hydrochloride

(87)2-amidino-5-[4-[[[(methoxycarbonyl)-methyl]-aminocarbonyl]-methyloxy]-phenyl]-pyrimidine-hydrochloride

(88)6-(4-amidinophenyl)-4-[[3-(methoxycarbonyl)-prop-2-en-yl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

(89)6-(4-amidinophenyl)-3-amino-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-pyridazine-hydrochloride

(90)6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[[[1-(methoxycarbonyl)-2-phenylethyl]-aminocarbonyl]-methyl]-(2H)-pyridazin-3-one-hydrochloride

(91)6-(4-amidinophenyl)-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-2-[[[1-(methoxycarbonyl)ethyl]-aminocarbonyl]-methyl]-(2H)-pyridazin-3-one-hydrochloride

(92)2-[4-[N-[[3-(methoxycarbonyl)-propyl]-carbonyl]-N-methylamino]-phenyl]-5-(N-methyl-amidino)-pyridine-hydrochloride

The imino ester is dissolved in absolute methanol and reacted with a20-fold excess of a methanolic methylamine solution.

(93)5-(4-amidinophenyl)-2-[[4-[(methoxycarbonyl)-methyl]-piperidino]-methyl]-pyrimidine-hydrochloride

(94)5-amidino-2-[4-[[4-(methoxycarbonyl)-butyl]-aminosulphonyl]-phenyl]-pyrimidine-hydrochloride

(95)5-(4-amidinophenyl)-2-[4-[(methoxycarbonyl)-methylidene]-piperidinocarbonyl]-pyrimidine-hydrochloride

(96)2-(4-amidinophenyl)-5-[4,4-bis-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine-hydrochloride

(97)1-(4-amidinophenyl)-5-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(1H)-pyridin-2-one-hydrochloride

(98)4-[4-[N-(n-butyl)-amidino]-phenyl]-1-[[[2-(methoxycarbonyl)ethyl]-aminocarbonyl]-methyl]-(1H)-pyridin-2-one-hydrochloride

The imino ester is taken up in absolute methanol and reacted with a20-fold excess of a methanolic n-butylamine solution.

(99)6-(4-amidinophenyl)-4-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

(100)6-(4-amidinophenyl)-4-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-2-[(morpholinocarbonyl)methyl]-(2H)-pyridazin-3-one

(101)2-(4-amidinophenyl)-4-methoxy-5-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyrimidine

(102)2-(4-amidinophenyl)-5-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-pyrimidine

(103)2-(4-amidinophenyl)-4-ethoxy-5-[N-[trans-4-(ethoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-pyrimidine

The starting material used is4-chloro-2-(4-cyanophenyl)-5-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-pyrimidine.The reaction is carried out in ethanol.

EXAMPLE 36-[4-[N-(Methoxycarbonyl)-amidino]-phenyl]-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

To a solution of 300 mg of6-(4-amidinophenyl)-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-onein a mixture of 10 ml of methylene chloride and 10 ml of methanol areadded 95 mg of methyl chloroformate. By the dropwise addition of 1Nsodium hydroxide solution the pH of the solution is maintained atbetween 8.5 and 9.0. The reaction is monitored by thin layerchromatography. After 11/2 hours another 0.1 ml of methyl chloroformateare added. After 3 hours the organic solvent is evaporated off, theaqueous phase remaining is diluted with water and extracted three timeswith methylene chloride. After the organic phase has been dried oversodium sulphate the solvent is evaporated off and the solids remainingare chromatographed over silica gel.

Yield: 290 mg (85% of theory), Mass spectrum: 470 (M+1)⁺ R_(f) value:0.58 (silica gel; methylene chloride/methanol=9:1)

The following compounds are obtained analogously:

(1)6-[4-[N-(ethoxycarbonyl)-amidino]-phenyl]-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Ethyl chloroformate is used.

Mass spectrum: 483 M⁺ R_(f) value: 0.54 (silica gel; methylenechloride/methanol=9:1)

(2)6-[4-[N-(methoxycarbonyl)-amidino]-phenyl]-4-[[cis-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one

Mass spectrum: 469 M⁺ R_(f) value: 0.73 (silica gel; methylenechloride/methanol=9:1)

(3)4-methoxy-2-[4-[N-(methoxycarbonyl)-amidino]-phenyl]-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine

Melting point: 193°-195° C., Mass spectrum: 469 M⁺ R_(f) value: 0.48(silica gel; methylene chloride/methanol=9:1)

(4)5-[4-[N-(methoxycarbonyl)-amidino]-phenyl]-2-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-pyrimidine

(5)4-[N-[trans-4-(benzyloxycarbonyl)-cyclohexyl]-N-methylaminocarbonyl]-6-[4-[N-(methoxycarbonyl)-amidino]-phenyl]-2-methyl-(2H)-pyridazin-3-one

The benzylester is used as starting compound.

(6)6-[4-[N-methoxycarbonyl)-amidino]-phenyl]-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

(7)6-[4-[[(N-acetyloxymethyl)-oxycarbonyl]-amidino]-phenyl]-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

Acetyloxymethyl-(4-nitrophenyl)-carbonate and N-ethyl-diisopropylamineare used.

(8)6-[4-[[(1-acetyloxy-ethyl)-oxycarbonyl]-amidino]-phenyl]-4-[[trans-4-(ethoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

(1-acetyloxy-ethyl)-(4-nitrophenyl)-carbonate andN-ethyl-diisopropylamine are used.

(9)2-[4-[N-(methoxycarbonyl)-amidino]-phenyl]-5-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-pyrimidine

(10)2-[4-[(diethylphosphono)-amidino]-phenyl]-5-[N-[trans-4-(methoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-pyrimidine

The reaction is carried out with diethylphosphate chloride intetrahydrofuran/water with the dropwise addition of sodium hydroxidesolution followed by chromatographic purification.

EXAMPLE 46-[4-(Aminomethyl)-phenyl]-4-[(trans-4-carboxy-cyclohexyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

A suspension of 1.50 g of4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-6-(4-cyanophenyl)-2-methyl-(2H)-pyridazin-3-oneand 0.5 g of Raney nickel in 500 ml of concentrated ammoniacal methanolis hydrogenated for 41/2 hours at ambient temperature under a hydrogenpressure of 5 bar. The catalyst is filtered off and the filtrate isevaporated down using a rotary evaporator. The solids remaining arechromatographed over silica gel. 1.0 g (66% of theory) of product areobtained. In order to prepare the hydrochloride 310 mg of the productare suspended in 150 ml of tetrahydrofuran. Ethereal hydrochloric acidis added dropwise thereto, followed by sufficient water to form asolution. The organic solvents are evaporated off. The precipitate issuction filtered, washed with a little water and dried at 80° C.

Yield: 290 mg (56% of theory), Melting point: sintering from 287° C.Mass spectrum: 384 M⁺ R_(f) value: 0.57 (silica gel; methylenechloride/methanol/conc. ammonia solution=4:1:0.25)

    ______________________________________                                        Calc.: × HCl × H.sub.2 O:                                                         C 54.73 H 6.20  N 12.76                                                                              Cl 8.08                                Found:          54.67   6.06    12.66  7.96                                   ______________________________________                                    

The following compounds are obtained analogously:

(1)6-[4-(aminomethyl)-phenyl]-2-benzyl-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

Mass spectrum: 460 M⁺ R_(f) value: 0.62 (silica gel; methylenechloride/methanol/conc. ammonia solution=2:1:0.25)

(2)5-aminomethyl-2-[4-[4-(carboxymethyl)-piperidino-carbonyl]-phenyl]-pyridin

EXAMPLE 56-[4-(Aminomethyl)-phenyl]-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-hydrochloride

A solution of 780 mg of6-[4-(aminomethyl)-phenyl]-4-[(trans-4-carboxycyclohexyl)-aminocarbonyl]-2-methyl-(2H)-pyridazin-2-onein a mixture of 400 ml of absolute methanol and 50 ml of etherealhydrochloric acid is stirred for 16 hours at ambient temperature. Thesolvent is evaporated off and the residue is chromatographed over silicagel.

Yield: 440 mg (50% of theory), Melting point: 175°-178° C. Massspectrum: 398 M⁺ R_(f) value: 0.28 (silica gel; methylenechloride/methanol=9:1)

The following compounds are obtained analogously:

(1)6-[4-(aminomethyl)-phenyl]-2-benzyl-4-[[trans-4-(methoxycarbonyl)-cyclohexyl]-aminocarbonyl]-(2H)-pyridazin-3-one-hydrochloride

Mass spectrum: 474 M⁺ R_(f) value: 0.64 (silica gel; methylenechloride/methanol/conc. ammonia solution=8:1:0.1)

(2)5-aminomethyl-2-[4-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-phenyl]-pyridine-hydrochloride

EXAMPLE 62-[4-[N-(Benzyloxycarbonyl)-amidino]-phenyl]-5-[4-[(benzyloxycarbonyl)-methyl]-4-hydroxy-piperidinocarbonyl]-pyrimidine

Prepared by reacting2-[4-[N-(benzyloxycarbonyl)-amidino]-phenyl]-5-carboxy-pyrimidine with1.2 equivalents of N,N-carbonyl-diimidazole in dimethylformamide at 5°C. followed by the addition of 1.2 equivalents of4-[(benzyloxycarbonyl)-methyl]-4-hydroxy-piperidine-hydrochloride and1.2 equivalents of N-methylmorpholine at ambient temperature.

EXAMPLE 72-(4-Amidinophenyl)-5-[4-(carboxymethyl)-4-hydroxypiperidinocarbonyl]-pyrimidine

Prepared by hydrogenation of2-[4-[N-(benzyloxycarbonyl)-amidino]-phenyl]-5-[4-[(benzyloxycarbonyl)-methyl]-4-hydroxy-piperidino-carbonyl]-pyrimidinein methanol in the presence of 10% palladium on charcoal at ambienttemperature under a hydrogen pressure of 5 bar.

The following compound is obtained analogously:

(1) 4-[N-(trans-4-carboxy-cyclohexyl)-N-methyl-aminocarbonyl]-6-[4-[N-(methoxycarbonyl)-amidino]-phenyl]-2-methyl-2H-pyridazin-3-one

EXAMPLE 82-(4-Amidinophenyl)-5-[4-[[(pyridin-3-ylmethyl)-oxycarbonyl]-methyl]-piperidinocarbonyl]-pyrimidine

2-(4-amidinophenyl]-5-[4-(carboxymethyl)-piperidino-carbonyl]-pyrimidineis esterified with a 12-fold excess of 3-hydroxymethyl-pyridine and a15-fold excess of methanesulphonic acid in dimethylformamide.

The following compound is obtained analogously:

(1)6-(4-amidinophenyl)-4-[N-[trans-4-(benzyloxy-carbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-2-methyl-(2H)-pyridazin-3-one-toluenesulphonate

The work is done in benzyl alcohol as solvent using 2 equivalents oftoluenesulphonic acid.

EXAMPLE 96-(4-Amidinophenyl)-2-benzyl-4-[[trans-4-(isopropoxy-carbonyl)-cyclohexyl]-aminocarbonyl]-(2H)-pyridazin-3-one

A solution of 130 mg of6-(4-aminophenyl)-2-benzyl-4-[(trans-4-(carboxycyclohexyl)-aminocarbonyl]-(2H)-pyridazin-3-onein 30 ml of isopropanol saturated with hydrogen chloride is stirred for30 hours at ambient temperature. The solvent is evaporated down underreduced pressure and the residue is chromatographed over silica gel.

Yield: 40 mg (20% of theory), Mass spectrum: 516 (M+H)⁺ R_(f) value:0.12 (silica gel; methylene chloride/isopropanol/conc. ammoniasolution=4:1:0.25)

The following compounds are obtained analogously:

(1)6-(4-amidinophenyl)-4-[[trans-4-(cyclohexyloxy-carbonyl)-cyclohexyl]-aminocarbonyl]-2-[(morpholino-carbonyl)-methyl]-(2H)-pyridazin-3-one

The reaction is carried out in a mixture of cyclohexanol/methylenechloride saturated with hydrogen chloride.

(2)6-(4-amidinophenyl)-4-[[trans-4-(cyclohexyl-methyloxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

The reaction is carried out in a mixture of cyclohexylmethanol/methylenechloride saturated with hydrogen chloride.

(3) 6-(4-amidinophenyl)-4-[[trans-4-(ethoxycarbonyl)-cyclohexyl]-aminocarbonyl]-2-[(morpholinocarbonyl)-methyl]-(2H)-pyridazin-3-one

The reaction is carried out in ethanol saturated with hydrogen chloride.

(4)2-(4-amidinophenyl)-5-[N-methyl-N-[trans-4-(isopropoxycarbonyl)-cyclohexyl]-aminocarbonyl]-pyrimidine

(5)2-(4-amidinophenyl)-5-[N-[trans-4-(cyclohexyloxy-carbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-pyrimidine

The reaction is carried out in a mixture of cyclohexanol/methylenechloride saturated with hydrogen chloride.

(6)2-(4-amidinophenyl)-5-[N-[trans-4-(cyclopentylmethoxycarbonyl)-cyclohexyl]-N-methyl-aminocarbonyl]-pyrimidine

The reaction is carried out in a mixture ofcyclopentylmethanol/methylene chloride saturated with hydrogen chloride.

EXAMPLE 102-[4-(Aminomethyl)-phenyl]-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-(3H)-pyrimidin-4-one-hydrochloride

A suspension of 670 mg of2-(4-cyanophenyl)-5-[4-[(methoxycarbonyl)-methyl]-piperidinocarbonyl]-(3H)-pyrimidin-4-oneand 100 mg of 10% palladium on charcoal in 125 ml of methanol and 20 mlof ethereal hydrochloric acid is hydrogenated for 3 hours at ambienttemperature under a hydrogen pressure of 3 bar. The catalyst is filteredoff and the filtrate is evaporated down under reduced pressure. Thesolids remaining are triturated with ether and suction filtered.

Yield: 740 mg (100% of theory), Melting point: 205° C. (decomp.) R_(f)value: 0.18 (silica gel; methylene chloride/methanol/conc. ammoniasolution=4:1:0.25)

EXAMPLE 11

Dry ampoule containing 2.5 mg of active substance per 1 ml

Composition:

    ______________________________________                                        Active substance       2.5    mg                                              Mannitol               50.0   mg                                              Water for injections ad                                                                              1.0    ml                                              ______________________________________                                    

Preparation:

The active substance and mannitol are dissolved in water. Afterpackaging, the ampoules are freeze-dried.

The solution ready for use is made up with water for injections.

EXAMPLE 12

Dry ampoule containing 35 mg of active substance per 2 ml

Composition:

    ______________________________________                                        Active substance       35.0   mg                                              Mannitol               100.0  mg                                              Water for injections ad                                                                              2.0    ml                                              ______________________________________                                    

Preparation:

The active substance and mannitol are dissolved in water. Afterpackaging, the ampoules are freeze-dried.

The solution ready for use is made up with water for injections.

EXAMPLE 13

Tablet containing 50 mg of active substance

Composition:

    ______________________________________                                        (1) Active substance   50.0 mg                                                (2) Lactose            98.0 mg                                                (3) Corn starch        50.0 mg                                                (4) Polyvinylpyrrolidone                                                                             15.0 mg                                                (5) Magnesium stearate 2.0 mg                                                                        215.0 mg                                               ______________________________________                                    

Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granules. From this mixture,compressed tablets are made, which are biplanar, facetted on both sidesand notched on one side. Diameter of tablets: 9 mm.

EXAMPLE 14

Tablet containing 350 mg of active substance

Composition:

    ______________________________________                                        (1) Active substance   350.0 mg                                               (2) Lactose            136.0 mg                                               (3) Corn starch        80.0 mg                                                (4) Polyvinylpyrrolidone                                                                             30.0 mg                                                (5) Magnesium stearate 4.0 mg                                                                        600.0 mg                                               ______________________________________                                    

Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueoussolution of (4). (5) is added to the dried granules. From this mixture,compressed tablets are made, which are biplanar, facetted on both sidesand notched on one side. Diameter of tablets: 12 mm.

EXAMPLE 15

Capsules containing 50 mg of active substance

Composition:

    ______________________________________                                        (1) Active substance   50.0 mg                                                (2) Dried corn starch  58.0 mg                                                (3) Powdered lactose   50.0 mg                                                (4) Magnesium stearate 2.0 mg                                                                        160.0 mg                                               ______________________________________                                    

Preparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with thorough mixing.

The powdered mixture is packed into hard gelatin oblong capsules, size3, in a capsule filling machine.

EXAMPLE 16

Capsule containing 350 mg of active substance

Composition:

    ______________________________________                                        (1) Active substance   350.0 mg                                               (2) Dried corn starch  46.0 mg                                                (3) Powdered lactose   30.0 mg                                                (4) Magnesium stearate 4.0 mg                                                                        430.0 mg                                               ______________________________________                                    

Preparation:

(1) is triturated with (3). This trituration is added to the mixture of(2) and (4) with thorough mixing.

The powdered mixture is packed into hard gelatin oblong capsules, size0, in a capsule filling machine.

What is claimed is:
 1. A heterobiaryl derivative of the formula

    R.sub.1 NH--X.sub.1 --X.sub.2 --X.sub.3 --Y.sub.1 --Y.sub.2 --Y.sub.3 --Y.sub.4 --E                                             (I)

wherein R₁ denotes a hydrogen atom, a C₁₋₄ -alkyl, group or analkoxycarbonyl group having a total of 2 to 5 carbon atoms optionallyphenyl-substituted in the alkoxy moiety, a phosphono group, anO-alkyl-phosphono or dialkylphosphoryl group wherein each alkyl moietycontains 1 or 2 carbon atoms, or an R'--CO--O--(R"CH)--O--CO-- group,whereinR' represents a C₁₋₄ -alkyl group, or a C₅₋₆ -cycloalkyl groupand R" denotes a hydrogen atom or a methyl group, X₁ represents a C₁₋₂alkylene group, or --C(═NH)-- group, X₂ represents a phenylene, group,or a phenylene group substituted by a fluorine, chlorine, or bromineatom or by a C₁ -C₂ alkyl, amino, hydroxy or C₁ -C₂ alkoxy group X₃represents a pyridinylene, pyrazinylene, pyrimidinylene orpyridazinylene group each optionally substituted in the carbon skeletonby a fluorine, chlorine or bromine atom or by a C₁ -C₂ alkyl, amino,hydroxy or C₁ -C₂ alkoxy group, Y₁ represents a bond, Y₂ represents abond, Y₃ represents a 1,4-piperazinylene group, Y₄ represents a straightchained or branched C₁₋₄ -alkylene group, and E represents a sulpho,5-tetrazolyl, phosphono, O-methyl-phosphono, R'--CO--O--(R"CH)--O--CO--,R'"CO-- or R'O--CO--O--(R"CH)--O--CO-- group, whereinR' and R" are ashereinbefore defined and R'" denotes a hydroxy group, a C₁₋₅ -alkoxygroup in which the alkoxy moiety may be substituted in the 1-, or 2-position by a phenyl or pyridyl group or in the 2- or 3-position by apyrrolidino, piperidino, hexamethyleneimino, morpholino orthiomorpholino group, a C₄₋₇ -cycloalkoxy group, a cycloalkylalkoxygroup having 4 to 7 carbon atoms in the cycloalkyl moiety and 1 to 3carbon atoms in the alkoxy moiety, or a phenylallyloxy group, atautomer, stereoisomer and mixture thereof or a salt thereof.
 2. Aheterobiaryl derivative as recited in claim 1 whereinR₁ represents ahydrogen atom, a C₁₋₄ -alkyl group, an alkoxycarbonyl group having atotal of 2 to 5 carbon atoms, a benzyloxycarbonyl, dimethylphosphoryl,diethylphosphoryl or R'--CO--O--(R"CH)--O--CO-- group, whereinR'represents a methyl or ethyl group and R" represents a hydrogen atom ora methyl group, X₁ represents a methylene group or a --C(═NH)-- group,X₂ represents a phenylene, group or a phenylene group substituted by afluorine, chlorine or bromine or by a methyl, hydroxy, methoxy, ethoxy,amino or dimethylamino group, X₃ represents a pyridinylene,pyrazinylene, pyrimidinylene or pyridazinylene group each of which maybe substituted in the carbon skeleton by a fluorine, chlorine or bromineor by a methyl, hydroxy, methoxy, ethoxy, amino or dimethylamino group,Y₁ represents a bond, Y₂ represents a bond, Y₃ represents a1,4-piperazinylene group, Y₄ represents a straight-chained or branchedC₁₋₄ -alkylene group, and E represents R'"CO-- group, wherein R'"represents a hydroxy group, a C₁₋₄ -alkoxy group, a cycloalkoxy orcycloalkoxymethoxy group, each having 5 or 6 carbon atoms in thecycloalkoxy moiety or a benzyloxy or pyridylmethoxy group, a tautomer,stereoisomer or mixtures thereof, or a salt thereof.
 3. A heterobiarylderivative as recited in claim 1, whereinR₁ represents a hydrogen atom,or a alkoxycarbonyl group with a total of 2 or 3 carbon atoms, X₁represents a methylene group or a --C(═NH)-- group, X₂ represents aphenylene, group or a phenylene group substituted by a fluorine,chlorine or bromine or by a methyl or methoxy group, X₃ represents apyridinylene, pyrazinylene, pyrimidinylene or pyridazinylene group eachof which may be substituted in the carbon skeleton by a fluorine,chlorine or bromine or by a methyl or methoxy group, Y₁ represents abond, Y₂ represents a bond, Y₃ represents a 1,4-piperazinylene, Y₄represents an alkylene group having 1 or 2 carbon atoms, and Erepresents a carboxy group or an alkoxycarbonyl group having a total of2 to 4 carbon atoms, a tautomer, stereoisomer or mixtures thereof, or asalt thereof.
 4. A heterobiaryl derivative as recited in claim 1whereinR₁ represents a hydrogen atom or an alkoxycarbonyl group with atotal of 2 or 3 carbon atoms, X₁ represents a methylene group or a--C(═NH)-- group, X₂ represents a phenylene group, or phenylene groupsubstituted by a fluorine, chlorine or bromine or by a methyl or methoxygroup, X₃ represents a pyridazinylene, pyrimidinylene or pyridazinylenegroup each of which may be substituted in the carbon skeleton by afluorine, chlorine or bromine or by a methyl or methoxy group, Y₁represents a bond, Y₂ represents a bond, Y₃ represents a1,4-piperazinylene group, Y₄ represents an alkylene group having 1 or 2carbon atoms, and E represents a carboxy group or an alkoxycarbonylgroup having a total of 2 to 4 carbon atoms, a tautomer, stereoisomer ormixtures thereof, or a salt thereof.
 5. A heterobiaryl derivative asrecited in claim 1, whereinR₁ represents a hydrogen atom or analkoxycarbonyl group having a total of 2 or 3 carbon atoms, X₁represents a methylene group or a --C(═NH)-- group, X₂ represents aphenylene group, or a phenylene group substituted by a fluorine,chlorine or bromine or by a methyl or methoxy group, X₃ represents apyrimidinylene or pyridazinylene group, Y₁ represents a bond, Y₂represents a bond, Y₃ represents a 1,4-piperazinylene group, Y₄represents a methylene group or ethylene group, and E is a carboxy groupor an alkoxycarbonyl group with a total of 2 or 3 carbon atoms, atautomer, stereoisomer or mixtures thereof, or a salt thereof.
 6. Aheterobiaryl derivative as recited in claim 1, whereinR₁ represents ahydrogen atom or an alkoxycarbonyl group having a total of 2 or 3 carbonatoms, X₁ represents a methylene group or a --C(═NH)-- group, X₂represents a phenylene group, X₃ represents a pyrimidinylene orpyridazinylene group, Y₁ represents a bond, Y₂ represents a bond, Y₃represents a 1,4-piperazinylene group, Y₄ represents a methylene orethylene group, and E represetns a carboxy group or an alkoxycarbonylgroup with a total or 2 or 3 carbon atoms, a tautomer, stereoisomer ormixtures thereof, or a salt thereof. 7.6-(4-amidinophenyl)-3-[4-(carboxymethyl)-piperazino]-pyridazine or asalt thereof.